Module 16 - Pharmacotherapy For Psychiatric Disorders

Geriatric
Pharmacy Review Module 16 Pharmacotherapy for Psychiatric Disorders
Accreditation Information
ASCP is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.
This home study web activity has been assigned 2.25 credit hours. ACPE UPN: 0203-0000-10-096-H01-P Release Date: 6/16/2010 Expiration Date: 7/1/2013
To receive continuing education credit for this course, participants must complete an on-line evaluation form and pass the online assessment with a score of 70% or better. If you do not receive a minimum score of 70% or better on the assessment, you are permitted 4 retakes. After passing the assessment, you can print and track your continuing education statements of credit online.
Geriatric Pharmacy Review courses have not yet been approved for Florida consultant pharmacy continuing education.
Copyright 2011 American Society of Consultant Pharmacists
Current Content Experts
Kevin Chamberlin, PharmD Assistant Clinical Professor University of Connecticut Health Center
Casey K Gardner, PharmD Clinical Assistant Professor of Pharmacy Practice College of Pharmacy & Health Services Campbell University
Kristen Meyer, PharmD Drake University School of Pharmacy
Christopher J. Thomas, PharmD Clinical Pharmacist Veterans Affairs Medical Center
Legacy Content Experts
Jonathan P. Lacro, Pharm.D., FASHP, BCPS, BCPP Program Manager and Clinical Pharmacist in Psychiatry VA San Diego Healthcare System & Associate Clinical Professor of Psychiatry University of California, San Diego & Research Scientist Veterans Medical Research Foundation
Sean M. Jeffery, PharmD, CGP, FASCP Assistant Clinical Professor & Clinical Pharmcy Specialist, Geriatrics VA Connecticut Healthcare System
Faculty Disclosures
Kevin W. Chamberlin has no relevant financial relationships to disclose. Casey K Gardner, PharmD, has no relevant financial relationships to disclose. Sean M. Jeffery has no relevant financial relationships to disclose. Jonathan P. Lacro has no relevant financial relationships to disclose. Kristen Meyer, PharmD, has no relevant financial relationships to disclose. Christopher J. Thomas, PharmD, has no relevant financial relationships to disclose.
Anxiety
By the end of this review concept, you will be able to: Differentiate different types of anxiety disorders. Describe the epidemiology and etiology of generalized anxiety disorder. List drugs that can cause anxiety. Describe signs and symptoms of generalized anxiety disorder. Describe diagnostic and treatment protocols for patients with anxiety disorders. Identify pharmacological treatment options for patients with anxiety disorders. Describe indications, contraindications, dosing, adverse effects, and drug-drug interactions for agents commonly
used to treat anxiety disorders
Types of Anxiety Disorders

Panic disorder: Extreme fear, striking without warning and peaking within 10 minutes, usually accompanied with tachycardia, sweatiness, faintness or dizziness. Phobias: Specific phobia: Disabling fear of something that poses no actual danger Social phobia: Fear of embarrassment or humiliation in social settings Obsessive-Compulsive Disorder (OCD): Unwanted thoughts and compulsive behaviors (rituals) which are difficult to stop or control Post-traumatic Stress Disorder (PTSD): Stress lasting at least 1 month after a traumatic event. The symptoms usually begin within 3 months but occasionally begins years later. People with PTSD may be easily startled, emotionally numb, irritable and they may have difficulty feeling affectionate. Anxiety disorders are among the most common diagnosable conditions in older adults. Yet the prevalence of anxiety disorders is lower for the elderly than for other age groups. Despite these differences, anxiety disorders continue to be the most prevalent of psychiatric disorders in the elderly. In community samples, the 6-month prevalence of all anxiety disorders was 19.7% and the lifetime prevalence was 34.1%. Panic disorder involves sudden extreme fear, striking without warning. Symptoms generally reach a peak within ten minutes. Panic disorders affect about 6 million American adults and twice as many women as men are affected. Phobias are many and varied. Two phobias that are of particular interest in the elderly population are the disabling fear associated with something that presents no real danger, and the fear of embarrassment or humiliation in social settings. With both phobias, increased avoidance behavior is observed. Obsessive-compulsive disorder involves unwanted thoughts or obsessions and compulsive behaviors that are difficult to stop or control. Obsessivecompulsive disorder is often a chronic, relapsing illness. It affects about 2.2 million Americans. Post-traumatic stress disorder can occur three months or more after the traumatic event. Symptoms must last more than one month to be considered a post-traumatic stress disorder. It affects abut 7.7 million Americans
Types of Anxiety Disorders
Anxiety disorders are among the most common diagnosable conditions in older adults. Yet the prevalence of anxiety disorders is lower for the elderly than for other age groups. Despite these differences, anxiety disorders continue to be the most prevalent of psychiatric disorders in the elderly. In community samples, the 6-month prevalence of all anxiety disorders was 19.7% and the lifetime prevalence was 34.1%. Panic disorder involves sudden extreme fear, striking without warning. Symptoms generally reach a peak within ten minutes. Panic disorders affect about 6 million American adults and twice as many women as men are affected. Phobias are many and varied. Two phobias that are of particular interest in the elderly population are the disabling fear associated with something that presents no real danger, and the fear of embarrassment or humiliation in social settings. With both phobias, increased avoidance behavior is observed. Obsessive-compulsive disorder involves unwanted thoughts or obsessions and compulsive behaviors that are difficult to stop or control. Obsessive-compulsive disorder is often a chronic, relapsing illness. It affects about 2.2 million Americans. Post-traumatic stress disorder can occur three months or more after the traumatic event. Symptoms must last more than one month to be considered a post-traumatic stress disorder. It affects abut 7.7 million Americans
Generalized Anxiety Disorder (GAD)

Epidemiology: Most common anxiety disorder in elderly Affects almost twice as many women as men Excessive worrisome thoughts and tension beyond what the situation dictates The affected are often unaware that anxiety is more intense than the situation calls for Symptoms persist > 6 months Commonly presents with other comorbid conditions like depression or other psychiatric conditions Etiology: High levels of serotonin and norepinephrine Occurs during course of other psychiatric disorders Depression Dementia Schizophrenia Related to a general medical condition Cardiovascular disorders Pulmonary disorders Endocrine disorders (hyperthyroidism) Amine-secreting tumors Neurologic disorders (delirium & dementia) Related to drug therapy
Generalized Anxiety Disorder (GAD)

Related to social, medical and financial issues Financial restriction (elderly on fixed income) Loss of friends, family and spouse
The most common anxiety disorder in the elderly population is generalized anxiety disorder. This disorder affects more women than men, and is characterized by excessive worrisome thoughts and tensions that persist for at least six months. Estimates of the prevalence of generalized anxiety disorder in the older population ranges from 1% to 9%, with some references identifying as high as 20%. There is a general consensus that generalized anxiety disorder, like other anxiety disorders, is less common in the elderly population than in the adult population. Like most anxiety disorders, generalized anxiety disorder results in higher than normal levels of serotonin and norepinephrine in the brain. It can be caused by a number of factors such as psychiatric illness, traumatic events, loss of freedom, loss of support systems, social isolation and a variety of cardiovascular, pulmonary, endocrine and neurologic disorders. Various medications can also induce anxiety, worsening the underlying medical condition.
Drugs and Medical Conditions Associated with Anxiety

Sympathomimetics (e.g. pseudoephedrine, phenylephrine) Methylxanthine derivatives (theophylline, caffeine) Thyroid hormone replacement agents Corticosteroids Stimulants (e.g. dextroamphetamine, methylphenidate) Digitalis Antidepressants Anticholinergics Antihypertensives Drug withdrawal- caffeine, alcohol, benzodiazepines, antidepressants, sedative hypnotics, nicotine Antipsychotic-related akathisia Chronic obstructive lung disease Heart failure Stroke Parkinsons disease
On your screen you see a partial list of common agents and general medical conditions associated with anxiety. Many agents like the sympathomimetics and methylxanthine derivatives like theophylline are very stimulating and can exacerbate underlying anxiety disorder. In addition, some of these medications are used in conditions already associated with anxiety, for example the use of theophylline in patients with COPD or digitalis in heart failure patients.
Signs and Symptoms of Generalized Anxiety Disorder

Fatigue Trembling Muscle tension Headache Nausea Fearfulness Nervousness Insomnia Hyperventilation Irritability Difficulty concentrating
Signs and symptoms of generalized anxiety disorder include fatigue, muscle tension, and nausea. Many of these symptoms may last for more than six months. These signs and symptoms are similar to what patients might experience during a panic attack. The difference resides in the intensity and rapid onset of the symptoms during the panic attack. Additionally, panic attacks appear less common in the elderly. Determining whether the patient is experiencing generalized anxiety disorder or major depressive disorder is difficult because both of these disorders share symptoms (e.g. fatigue, difficulty concentration and sleep disturbances) and depression and generalized anxiety are frequently co-occurring. Generalized anxiety will not present with anhedonia, which is a core feature of major depressive disorder. Typically a patient with generalized anxiety will be seen by a primary care physician and present with unexplained physical symptoms (e.g. aches, pains, fatigue, gastrointestinal symptoms).
Diagnosing Generalized Anxiety Disorder

Confirm symptoms Identify duration of symptoms Rule out other medical conditions Depression Other psychiatric disorders Use laboratory tests CBC with differential Vitamin B12 levels Serum glucose levels Folate levels Thyroid function tests Serum calcium levels Obtain a thorough history from both patient and caregivers
Physical exam Anxiety assessment scales include: Hamilton Anxiety Scale Anxiety Status Inventory Sheehan Patient Rated Anxiety Scale Zung Self-rating Anxiety Scale Beck Anxiety Inventory
In diagnosing anxiety disorders, symptoms should be confirmed and the duration of symptoms identified. The patient should be thoroughly examined, and relevant laboratory tests performed to rule out the common medical causes of anxiety or other medical conditions. A thorough history should be obtained from both the patient and caregivers. Appropriate treatment of underlying physiologic illness may eliminate or significantly decrease anxiety symptoms. Both anxiety and depression assessment scales are helpful in determining the severity of these disorders. Anxiety assessment scales include the Hamilton Anxiety Scale and Anxiety Status Inventory, which are clinician rated, and the Sheehan Patient Rated Anxiety Scale, Zung Self-rating Anxiety Scale and Beck Anxiety Inventory,, which are all patientrated. Clinician-rated scales are preferred in long-term care settings.
Treatment of Generalized Anxiety Disorder

Goals: Decrease the severity and frequency of symptoms Increase the patients overall level of functioning Therapeutic Options: Psychotherapy Alone: Behavioral therapy: change actions through breathing & gradual desensitization Cognitive-behavioral therapy: change thinking patterns and reactions Psychotherapy + Pharmacotherapy The ultimate goals of treatment for patients with anxiety disorders are to decrease the severity and frequency of symptoms and increase the patients overall level of functioning. Non-drug treatment for generalized anxiety disorder generally involves psychotherapy as monotherapy or combined with drug therapy. Psychotherapy includes behavioral therapy, which works to change the patients responses through breathing exercises and desensitization to the trigger, and cognitive-behavioral therapy, which focuses on changing the patients thinking patterns and reactions. Due to the older adults potential for adverse drug reactions, psychotherapy may be the preferred method to try first, but pharmacotherapy is still the first choice in treating anxiety in the elderly.
Pharmacotherapy for Generalized Anxiety Disorder

Benzodiazepines Lorazepam (Ativan) Oxazepam (Serax) Alprazolam (Xanax) Other benzodiazepines (diazepam, clonazepam, etc.)** Nonbenzodiazepine anxiolytics Buspirone (BuSpar) Antihistamines (e.g., hydroxyzine pamoate)** Beta blockers (e.g., propranolol)** Antidepressants TCAs** SSRIs SNRIs (e.g. venlafaxine) Other agents ** Not recommended as first line agents in the elderly The general drug classes for treating generalized anxiety disorder in the elderly include benzodiazepines with short and intermediate half-lives, and nonbenzodiazepine anxiolytics, which include buspirone, hydroxyzine pamoate and beta blockers. Antihistamines, beta blockers and tricyclic antidepressants are effective for treating anxiety, but their side effects make them unsuitable as first line agents for the geriatric population.
Treatment of Anxiety Disorders with Benzodiazepines

Dosing: Lorazepam: 0.25-4 mg/day; maximum with dementia - 2 mg/day Oxazepam: 10-90 mg/day; maximum with dementia - 30 mg/day Alprazolam: 0.125-4 mg/day; maximum with dementia - 0.75 mg/day Duration of Treatment: not to exceed 4 months Adverse Drug Reactions: Sedation Short term memory impairment Dysarthria Ataxia Falls Constipation Paradoxical reactions Drowsiness/fatigue Dependence
Benzodiazepines with short and intermediate half-lives can effectively treat symptoms associated with generalized anxiety disorder. Usual geriatric dosing ranges are shown on your screen; lower maximum doses are recommended when using these agents to treat anxiety associated with dementia syndromes. Recommended duration of therapy is no longer than four months, although some patients may require longer-term therapy. For those patients with dementia who are manifesting anxiety symptoms, it is recommended to stop the medication as soon as possible because the anxiety symptoms may be transient. Benzodiazepines should be used cautiously in the elderly because of their increased sensitivity to adverse effects such as sedation, short-term memory impairment, dysarthria, ataxia and falls as well as their decreased pulmonary reserve and potential tendency towards hypoxia.
Discontinuation of Benzodiazepine Treatment

Monitor withdrawal symptoms: Psychomotor restlessness Agitation Insomnia Muscle tension Nausea/vomiting Ataxia Loss of appetite Tonic-clonic seizures Delirium Rebound/relapse of symptoms Taper dosage gradually: 4-6 weeks for those taking agent daily for > 1 mo. Cognitive behavioral therapy may be useful in assisting with withdrawal To determine mg dose tapered weekly: divide total daily dose by 5 (round to nearest commercially available dosage form, if necessary). (Psychotropic Drug Handbook 7th ed.) If withdrawal is problematic, slow weekly tapering to 1/8 of total daily dose With long term use, tolerance develops to the sedative effects but not to the anxiolytic and anti-panic properties of these drugs. A careful tapering schedule can help avoid uncomfortable withdrawal symptoms such as restlessness, agitation, and insomnia. Gradually taper over two to four weeks for patients who have received treatment on a daily basis for one month or more. More severe withdrawal symptoms may occur in those tapered too quickly from short half-life agents. If withdrawal symptoms are problematic, slow the weekly tapering schedule to one eighth of the total daily dose for the last several weeks.
Drug-Drug Interactions with Benzodiazepines

Pharmacodynamic Interactions: Potentiation of sedation and respiratory depression with other sedating agents With overdose, benzodiazepine-alcohol combination may result in death Pharmacokinetic Interactions: More common with alprazolam, since metabolized by CYP450 3A4 hepatic isoenzyme system In patients taking alprazolam and a metabolic inhibitor or inducer, monitor for ADRs Drugs that decrease alprazolam clearance: itraconazole and ketoconazole, diltiazem, erythromycin, indinavir, ritonavir, nefazodone, fluvoxamine, fluoxetine, cimetidine Drugs that increase alprazolam clearance: carbamazepine Lorazepam and oxazepam not implicated
The most common pharmacodynamic interaction is potentiation of sedation and respiratory depression in combination with other sedating agents like alcohol, antidepressants, and antipsychotics. In overdose, the benzodiazepine - alcohol combination has often resulted in death. Pharmacokinetic drug interactions are more commonly observed with alprazolam since it is metabolized by the CYP-450 -3A4 hepatic isoenzyme system. Patients receiving alprazolam and a metabolic inhibitor or inducer should be closely monitored for adverse effects or therapeutic failure. Drugs that inhibit CYP-450-3A4 and decrease alprazolam clearance are shown in the table along with those that increase the agents clearance. Lorazepam and oxazepam are eliminated by conjugation and are not implicated in significant pharmacokinetic drug interactions.
Treatment of Anxiety Disorders with Buspirone (BuSpar)

Indications: Patients who cannot tolerate effects of benzodiazepines Contraindications: Patients with panic disorder Onset: slow Dosing: Range: 15-45 mg/day Beginning therapy: 5 mg BID-TID Usual maintenance: 30 mg/day Max dose of 60 mg/day Adverse Drug Reactions: Reduced risk of falls when compared to benzodiazepines Dizziness Nausea Headaches Restlessness Nervousness
Buspirone is an alternative treatment for general anxiety disorder in patients who cannot tolerate the adverse effects associated with benzodiazepines. The agent lacks the sedative, anticonvulsant, muscle relaxant and dependence properties of the benzodiazepines. Buspirone is not effective in panic disorder and may cause worsening of symptoms. Also, it is not cross-tolerant with benzodiazepines and will not block benzodiazepine withdrawal. It has a slow onset of action, and may be dosed at fifteen to forty-five milligrams per day. The elderly may have a reduced risk of falls with buspirone, but should be monitored for adverse effects such as dizziness, nausea, and headaches.
Drug-Drug Interactions with Buspirone
Pharmacodynamic Interactions: Contraindicated with MAO inhibitors Caution with serotonergic antidepressants Monitor for potentiation of adverse effects Pharmacokinetic Interactions: Increases bioavailability of haloperidol
Buspirone is contraindicated in combination with MAO inhibitors, and should be used with caution in combination with serotonergic antidepressants. Monitoring for potentiation of adverse effects such as nausea and restlessness is essential. Pharmacokinetically, buspirone has been noted to increase the bioavailability of haloperidol.
Indications for the Use of Antidepressants to Treat Anxiety Disorders

Patients who cannot tolerate or poorly respond to benzodiazepines or buspirone or who have other comorbid conditions such as depression or a panic disorder. The SSRIs and venlafaxine are still first line therapy to treat anxiety disorders in the elderly. Dosing: Venlafaxine: Initial 18.75-37.5 mg/day orally; dosage range: 75-300 mg/day Nefazodone: : Initial: 50 mg/day orally; dosage range: 300-550 mg/day Fluoxetine: Initial: 5-10 mg/day orally; dosage range: 10-80 mg/day Paroxetine: Initial: 10 mg/day orally; dosage range: 20-50 mg/day Adverse Drug Reactions: All of the antidepressants are now blackboxed for increase in the risk of suicide thinking in children, but it is cautioned to monitor everyone first starting out and with dosage increases. Venlafaxine: Headache, insomnia, somnolence, nausea, xerostomia,anorexia, diaphoresis, constipation, hypertension at doses above 100mg/day. Nefazodone: Headache, drowsiness, agitation, dizziness, xerostomia, nausea, constipation, weakness. Fluoxetine: Insomnia, headache, anxiety, nausea, diarrhea, xerostomia, anorexia, weakness, tremor, decreased libido. Paroxetine: Somnolence, insomnia, headache, dizziness, decreased libido, nausea, constipation, ejaculatory disturbances.

Contraindications and Concerns: Venlafaxine: May impair platelet aggregation leading to increased bleeding; may increase serum cholesterol; renal/hepatic impairment as it is cleared by these 2 routes and may need to use a lower dose; SIADH and hyponatremia have been seen in the elderly. Nefazodone: Active liver disease; previous liver injury due to past exposure to nefazodone; use in patients during acute recovery phase of MI; cases of life threatening hepatic failure have been reported, Fluoxetine: Use cautiously in the elderly; if rash of unknown cause develops, discontinue; may alter glycemic control; may alter platelet aggregation and increase risk of bleeding; may cause or exacerbate sexual dysfunction; may cause weight loss; SIADH and hyponatremia have been seen in the elderly Paroxetine: Use cautiously in the elderly; akathisia, SIADH and hyponatremia have been seen in the elderly; hepatic and renal impairment; may cause or exacerbate sexual dysfunction Drug Interactions: Venlafaxine: SSRIs, buspirone, other drugs that can increase serotonin as at risk for serotonin syndrome, CYP2D6 inhibitors, CYP3A4 inhibitors/inducers. Nefazodone: Concurrent therapy with alprazolam or triazolam (requires a 50% and a 75% dose reduction respectively), anything that may increase serotonin to increase risk of developing serotonin syndrome, calcium channel blockers, CYP2D6 inhibitors, CYP3A4 inhibitors/inducers/substrates. Fluoxetine: Other drugs that can increase serotonin as at risk for serotonin syndrome, benzodiazepines (may see increased levels leading to increased serum levels), CYP1A2 substrates, CYP2C9 inducers/inhibitors/substrates, CYP2D6 inhibitors/ substrates, digoxin, HMGCoA reductase inhibitors, NSAIDS, warfarin
Paroxetine: Other drugs that can increase serotonin as at risk for serotonin syndrome, anticoagulants/antiplatelets for increased risk of bleeding, CYP2B6 substrates, CYP2D6 inhibitors/substrates, When to consider: Patients taking benzodiazepines or buspirone who may benefit from adjunct therapy Except for TCAs, first line agents for Panic disorder Comorbid depression Obsessive-compulsive disorder Social phobia Nerve pain
Antidepressants are an alternative first line therapy for general anxiety disorders in patients who cannot tolerate or poorly respond to benzodiazepines or buspirone or who have another reason to not take them (such as increased risk for falls). Antidepressants can also be used to augment treatment in patients who partially respond to benzodiazepines or buspirone. Antidepressants, excluding TCAs, are first line agents in patients with panic disorder, comorbid depression with anxiety, obsessive-compulsive disorder, and social phobia.
Anxiolytic Agents and Approved Indications

Agent Benzodiazepines: Alprazolam Lorazepam Oxazepam yes yes yes ? no no yes no no ? no no ? no no GAD OCD Panic Attacks PTSD Social Phobia
Non-benzodiazepines Buspirone SSRIs: Citalopram Escitalopram no yes data no data data ? no ? no yes ? ? ? data
The table on your screen shows various agents and their indications for anxiety disorders. A yes signifies an FDA approved indication; a no signifies no approved use of the drug for that disorder. The term data indicates that there is evidence to support the drugs use, but it is not an FDA approved indication at this time.
Anxiolytic Agents and Approved Indications

Agent Fluoxetine Paroxetine Sertraline GAD ? yes data OCD yes yes yes Panic Attacks yes yes yes PTSD data yes yes Social Phobia ? yes yes
Other Antidepressants: Bupropion Mirtazapine Nefazodone Duloxetine Venlafaxine Other Medications: Gabapentin Pregabalin Tiagabine no data data no no no no no no no no data data ? no no data no data yes no data no no no no data data no data ? ? data no no no no data data data
No = not an FDA approved indication Yes = FDA approved indication Data = not FDA approved, but evidence supports use ? = inconclusive data
Summary: Selecting Appropriate Drug Therapy for Anxiety Disorders

Presence of cognitive impairment Comorbid medical illnesses Fall history Adverse effect profiles Risk of drug interactions Type of anxiety disorder being treated
Anxiety disorders are diagnosed in many geriatric patients. In selecting the appropriate drug therapy, one should consider the following patient-specific factors: presence of cognitive impairment and comorbid medical illnesses, history of falls, adverse effect profiles, the risk of drug interactions, and the type of anxiety disorder being treated. Primary therapeutic outcomes are amelioration of anxious symptoms and functional improvement.
Resources and References

For additional information, see: Alwahhabi F (2003). Anxiety Symptoms and Generalized Anxiety Disorder in the Elderly: A Review. Harvard Review Psychiatry 11(4): 180-193. Averill PM, Beck JG (2000). Posttraumatic stress disorder in older adults: a conceptual review. J Anxiety Disord 14:133-156. Beers, M.H & Berkow, R. (2000). Anxiety disorders. The Merck Manual of Geriatrics. 3nd edition Section 4, Psychiatric Disorders. Whitehouse Station, NJ: Merck Research Laboratories: 322-327. Blazer D, George L, Hughes D (1991). The epidemiology of anxiety disorders: an age comparison, in Anxiety in the Elderly: Treatment and Research. Edited by Salzman C, Lebowitz BD. New York, Springer, pp 89-96. Flint A. (2005). Generalized Anxiety Disorder in Elderly Patients: Epidemiology, Diagnosis, and treatment options. Drugs Aging 22(2):101-114. Folks, D. G., & Fuller, W. C. (1997). Anxiety disorders and insomnia in geriatric patients. Psychiatr Clin North Am; 20: 137-164. Hunt C, Slade T, Andrews G. (2004). Generalized Anxiety Disorder and Major Depressive Disorder Comorbidity in the National Survey of Mental Health and Well-Being. Depression and Anxiety; 20(1):23-31. Jackson CW (1995). Obsessive-compulsive disorder in elderly patients. Drugs and Aging 7:438-448. Lindesay J (1991). Phobic disorders in the elderly. Br J Psychiatry 159:531-541.

disorder: current status and future directions. Clinical Psychology Review 24:149-169. Neel, Armon B., Comorbid Disorders: Anxiety and Depression in the Nursing Home Resident, ASCP Clinical Consult, Supplement 4, 1996 Perry P. J., Alexander B, Liskow B. (1997) Management of Withdrawal - Anxiolytic-Hypnotics. In Psychotropic Drug Handbook, 7th ed. American Psychiatric Press. Washington DC: 577-578. Raj, B. Ashok, Corvea, Martha H., and Dagon, Eugene M. The Clinical Characteristics of Panic Disorder in the Elderly: A Retrospective Study http://www.psychiatrist.com/pasttoc/toc/backgrounds/540403.htm Richelson, E. (1997). Pharmacokinetic drug interactions of new antidepressants: a review of the effects on the metabolism of other drugs. Mayo Clin Proc; 72: 835-847. Sheikh JI, Cassidy EL (2000): Treatment of anxiety disorders in the elderly: issues and strategies. J of Anxiety Disorders 14:173-190. Stimmel, G. L. & Gutierrez, M. A. (1995). Psychiatric disorders. In: Delafuente, J. C. & Stewart, R. B. (Eds). Therapeutics in the elderly. 2nd ed. Cincinnati, OH: Harvey Whitney Books, 324-343. Neel, Armon B., Comorbid Disorders: Anxiety and Depression in the Nursing Home Resident, ASCP Clinical Consult, Supplement 4, 1996 NIMH, Anxiety Disorders Education Program NIMH, Anxiety Disorders Publication, rev 2006
Alcohol Abuse
Learning Objectives:
By the end of this review concept, you will be able to: Describe the prevalence and morbidity/mortality associated with alcohol abuse in the elderly. Compare the etiology of early-onset and late-onset alcohol abuse. Describe the physiological changes that occur as a result of alcohol abuse, and the resulting clinical signs and symptoms. Explain the difficulties in diagnosing alcohol abuse in the elderly, and describe tests and metabolic markers that may be useful in confirming diagnosis. Describe the process and some of the therapeutic options available for treating alcohol abuse. Describe drugs commonly used in the pharmacotherapy of alcohol abuse, including their use, effects, dosing, adverse reactions, monitoring protocols and drug-drug interactions. Explain the risks associated with combining alcohol with prescription medications.
Epidemiology of Alcohol Abuse in the Elderly

Prevalence: Community based surveys have estimated that problem drinking in older adults ranges from 1 to 15%, depending on the diagnostic criteria applied. Alcohol abuse is approximately four times more common among men than women ages 65 and older. Morbidity/Mortality: Increases as the population ages Confusion with symptoms of other conditions (e.g., depression, insomnia, poor nutrition) Obscuring of other medical conditions (e.g., TIAs, Alzheimer's)
Very few studies have focused on the incidence or prevalence of substance abuse among older adults, but the perception is that problems are more often associated with the improper use of alcohol and prescription drugs, as opposed to abuse of illicit drugs. Although older adults are believed to have the lowest rates of alcohol abuse as an age cohort, the prevalence of alcohol use and abuse in this group is clearly underestimated. As a group, elderly adults tend to drink less and have fewer alcohol-related problems than younger people do. However, because drinking patterns are relatively stable over time, persons who develop alcoholism early in life tend to carry the problem into late life unless treated. As the proportion of the aging population increases, the number of older people with alcohol related problems will increase, even if the prevalence remains the same. Also contributing to the increasing number of older adults with alcohol-related problems is the observation that approximately one-third of older adults will experience alcohol-use problems after the age of 60 years. Older adults with alcohol-related problems are at greater risk for morbidity and mortality. One reason for the higher morbidity and mortality associated with the disorder is that older adults who drink at high-risk levels have not been recognized as atrisk or as problem drinkers by health care personnel. Symptoms of alcohol abuse are often mistaken for other medical conditions such as depression, insomnia, and poor nutrition. Alcohol abuse can obscure the diagnosis of transient ischemic attacks and Alzheimers disease, often leaving these comorbid conditions undetected and untreated.
Etiology of Alcohol Abuse

Early onset (< 60 years) Late-onset (> 60years) Cause: Varies: boredom, depression, isolation
Clinicians distinguish between two elderly alcoholic populations-- those with early-onset alcohol problems and those with late onset alcohol problems that occur after the age of sixty. It has been suggested, but not substantiated, that a number of people develop later-onset alcoholism after they retire, due to feelings of depression, boredom, and social isolation. Alcoholrelated disabilities may play an important role in admitting a patient to a nursing home or psychiatric facility.
Physiological Changes Associated with Alcohol Abuse

Decreased alertness, judgment, coordination, reaction time Increased risk of falls, accidents, hip fractures Irreversible cognitive impairment CNS, heart, liver, kidney and stomach damage Increased risk of suicide
Excessive alcohol use is associated with several adverse health effects including greater risk for harmful drug interactions, injury, depression, memory problems, liver disease, cardiovascular disease, cognitive changes and sleep disturbances. Physiologically, alcohol decreases alertness, judgment, coordination and reaction time. It also increases the risk of falls and accidents, leading to a higher incidence of hip fractures and associated mortality in the elderly. Drinking heavily can result in irreversible cognitive impairment, and affect the heart, liver, kidneys and stomach. Moderate to heavy drinkers are approximately nine times more likely to die by suicide than by natural causes or injury.
Clinical Presentation of Alcohol Abuse

Signs and Symptoms: Cognitive impairment Depression Liver and pancreatic disease Unexplained trauma Neurologic problems Sleep disturbances Chronic obstructive pulmonary disease Classic skin lesions (later stages) Organic brain syndrome Visual acuity affected Ambulation affected Decreased skeletal density The clinical signs and symptoms commonly seen in elderly alcoholics include depression, sleep disturbances, and unexplained trauma. In addition, alcohol abuse can lead to nutritional and vitamin deficiencies, Wernickes encephalopathy, and Korsakoffs psychosis. Wernickes encephalopathy is characterized by mental sluggishness, restlessness, confusion, ambulatory difficulties, and ocular problems. Thiamine supplementation is the treatment of choice for Wernicke's encephalopathy and is usually initiated early in detoxification. 80% of the patients with Wernicke's encephalopathy that go untreated will develop Korsakoff's Psychosis. Korsakoff's psychosis is characterized by psychosis and amnesia. 25 to 50% of patients with Korsakoff's psychosis do not recover and require long term care. In general, elderly alcoholics also tend to have more medical problems than compared with non-alcoholic elderly. These comorbid conditions can adversely affect management and treatment of all conditions. Possible Sequelae: Korsakoffs psychosis Nutritional and vitamin deficiencies Wernickes encephalopathy
Diagnosis of Alcohol Abuse

Diagnosis is difficult because: It is rarely a presenting complaint. It may be detectable only indirectly. It is often overlooked due to underestimation of alcohols role in presenting conditions. Diagnosis may be obscured by other comorbid conditions. The patient may try to conceal condition. Symptoms may be attributed to aging. DSM-IV-TR criteria may not be applicable to older adults. Diagnosis of alcohol abuse is difficult for a variety of reasons. Because elderly alcoholics rarely seek treatment directly for their condition, alcohol abuse is more likely to be detected indirectly in patients seeking attention for other medical or psychiatric conditions. The diagnosis is often overlooked in this population due to the underestimation of alcohol's contributing role in medical and psychiatric illnesses. It may also be complicated due to existing comorbid psychiatric disorders such as depression and dementia. Patients are often able to conceal alcohol abuse and may attribute the symptoms to aging. Lastly, although widely used, older adults with alcohol-related problems may not meet the rigorous legal, social or psychological consequences as specified in the DSM-IV-TR diagnostic criteria for alcohol-related problems. For example, an older retired person with minimal familial responsibilities is unlikely to fail in ones major role obligations at work, school, or home.
Markers and Indicators of Alcohol Abuse

Consumption limits: No more than one standard drink per day or seven standard drinks per week No more than two standard drinks on any drinking day Less than 1 standard drink per day for women A standard drink is defined as one 12-oz bottle of beer, one 4-oz glass of wine, 1.5 oz (a shot) of liquor (e.g., vodka, gin, whiskey), or 4 oz of liqueur. Psychosocial Markers/Tests: SMAST-G (Short Michigan Alcohol Screening Test-Geriatric version) CAGE items (may not detect earlier stages) Metabolic Indicators: Increase in the following blood values with no other known cause should arouse suspicion of alcoholism: Mean corpuscular volume (MCV) (e.g., >97) (26% of patients) with round macrocytosis Serum gamma-glutamyltransferase (GGT) Uric acid (10% of patients) ALT and AST (48% of patients AST can be twice the ALT) Alkaline Phosphatase (ALP) (16% of patients) Bilirubin (13% of patients) Triglycerides
Markers and Indicators of Alcohol Abuse

Additionally, the following lab abnormalities may also occur: Hypoalbuminemia Increased clotting time
Since older adults have an increased sensitivity to alcohol compared to younger adults, alcohol use recommendations for older adults are generally lower than those set for adults under 65 years. The recommended amount of alcohol that persons over the age of 65 may consume is provided on the screen. Exceeding these recommendations by the National Institute of Alcohol Abuse and Alcoholism and the Center for Substance Abuse Treatments Treatment Improvement Protocol for older adults increases the risk of alcohol-related problems. Psychosocial tests and metabolic indicators help identify alcohol abuse and dependence. The Short Michigan Alcohol Screening Test-Geriatric version (SMAST-G) was developed specifically for older adults and is useful both as a screening tool and to track progress in treatment. The CAGE test, a widely used alcohol screening test, may not detect earlier stages of alcoholism. Metabolic indicators of alcohol abuse include liver function tests, which can detect hepatic injury, hypoalbuminemia which occurs secondary to increased alcohol consumption at the expense of proper nutrition, increased clotting time as a result of decreased intake of vitamin K containing foods and hepatic impairment and macrocytic anemia that is most often due to folic acid deficiency. Despite the numerous metabolic indicators suggesting alcohol abuse, it is important to remember that these tests have poor positive predictive ability.
Treatment of Alcohol Abuse

Treatment Process: Nonjudgmental confrontation Detoxification Intense educational and therapeutic activities Treatment Options: Total abstinence Abstinence with improved functioning Improved functioning but no abstinence Pharmacotherapy
The success rate for elderly adults being treated for alcohol abuse is not significantly different from that of the general population. Long term improvement can be seen in twenty-five percent of all alcoholics abstaining from alcohol for at least one year. The treatment process involves nonjudgmental confrontation and detoxification, followed by intense educational and therapeutic activities, such as an introduction to Alcoholics Anonymous. Treatment options include total abstinence, abstinence with improved functioning, overall improved functioning but no abstinence, and pharmacotherapy.
Using Psychosocial Therapy to Treat Alcohol Abuse

Individual Counseling Group Counseling
Psychosocial therapy can help treat alcohol abuse. Counseling, individually or in a group, tends to be behavior oriented, and addresses the defense mechanism of denial. Individual counseling can be costly, and is usually not covered by many insurance companies. Group therapy through Alcoholics Anonymous and other addiction-related support groups reinforces abstinent behavior and are especially effective if the settings are age-segregated.
Pharmacotherapy for Alcohol Abuse

Thiamine and Magnesium: Do not prevent symptoms of withdrawal Thiamine used to prevent Wernickes encephalopathy and Korsakoffs psychosis Magnesium used to prevent hypomagnesemia seen during alcohol withdrawal Benzodiazepines (e.g. chlordiazepoxide, lorazepam, diazepam): Used during detoxification Minimizes withdrawal seizures and delirium tremens (DTs) Disulfiram (Antabuse): Used with abstinence program Produces unpleasant reaction when alcohol is consumed (aka the Antabuse effect) Naltrexone (ReVia) Used with abstinence program Blocks pleasurable feelings associated with alcohol Acamprosate (Campral) Used with abstinence program Reduces anxiety and somatic complains during sobriety in effort to maintain abstinence
Pharmacotherapy for Alcohol Abuse

Pharmacological agents to treat alcoholism include thiamine, magnesium, benzodiazepines, disulfiram, and naltrexone. Thiamine and magnesium should be administered to all alcoholics going through alcohol withdrawal. 50 to 100 mg of IV thiamine prevents the serious, but rare, complications of Wernickes encephalopathy and Korsakoffs psychosis. It is administered before glucose administration. Because hypomagnesemia is common in patients going through alcohol withdrawal, magnesium should also be given to patients during this time. Other electrolyte and fluid imbalances should be addressed as well. Benzodiazepines are used during acute detoxification to prevent withdrawal seizures and delirium tremens. Disulfiram and naltrexone may be utilized as apart of an abstinence program. Disulfiram is aversive therapy and produces a severely unpleasant reaction when alcohol is ingested. Naltrexone blocks the pleasurable feelings associated with alcohol consumption. Both agents can cause severe hepato-toxicity and require careful monitoring throughout therapy. Acamprosate is a newer agent to help with maintenance of abstinence from EtOH. The mechanism of action of acamprosate is to help reduce anxiety and somatic symptoms during sobriety to reduce risk of relapse. Duration of therapy is considered to be for 1 year after sobriety is first achieved.
Treatment of Alcohol Abuse with Benzodiazepines

Use only to prevent withdrawal symptoms. Agents: Chlordiazepoxide (Librium) Lorazepam (Ativan) - preferred in elderly; also for hepatic dysfunction Oxazepam (Serax ) Diazepam (Valium) Dosing: Dosages and withdrawal protocols vary Dosing must be individualized and titrated to effect Taper quickly (over 5 days) PRN supplemental dosing usually required for breakthrough symptoms Adverse Drug Reactions: Dysarthria, sedation, respiratory depression Monitoring: Prophylaxis of withdrawal, including tonic-clonic seizures, DTs Short-acting benzodiazepines such as lorazepam or oxazepam are preferred over chlordiazepoxide and diazepam for the treatment of alcohol abuse in the elderly, especially elderly patients with significant hepatic dysfunction because of their favorable pharmacokinetic profiles. These agents have the advantage of being metabolized and excreted principally through the kidneys and may be more suitable for patients with poor hepatic function. They also do not have active intermediary metabolites that may accumulate. Dosages are titrated to individual effect. Withdrawal protocols vary, but generally mandate routine administration with supplemental dosing for breakthrough symptoms
Treatment of Alcohol Abuse with Disulfiram (Antabuse):

Effects: Marked toxic responses such as severe nausea, vomiting, flushing, palpitations May persist for 2 weeks after cessation Contraindications: Cardiovascular disease, diabetes, epilepsy, hepatic failure Dosing: Usual: 250 mg daily Range: 125 to 500 mg daily Adverse Drug Reactions: Hepatitis, peripheral neuropathy, heart failure Monitoring: At baseline: LFTs, bilirubin, CBC Repeat in 10 days Repeat q 6 months Counsel against use of alcohol and alcohol containing products
Disulfiram is useful in abstinence programs because it produces severely unpleasant reactions when alcohol is ingested. These reactions, which include severe nausea, vomiting, flushing, and palpitations, may persist for two weeks after cessation of therapy. Disulfiram is contraindicated in cardiovascular disease, diabetes, epilepsy, and hepatic failure. It should be used with extreme caution in elderly, since adverse effects include hepatitis, peripheral neuropathy, and heart failure. Liver function tests, bilirubin, and complete blood count should be assessed at baseline, re-assessed in ten days, and monitored every six months thereafter. It is important to counsel patient to remain abstinent throughout this period and avoid any product containing alcohol.
Disulfiram (Antabuse): Drug-Drug Interactions

Metronidazole: causes CNS toxicity Benzodiazepines: increases serum levels (lorazepam and oxazepam not affected) Phenytoin: increases serum levels Warfarin: increases serum levels; bleeding Theophylline: increases serum levels
Disulfiram interacts with other drugs and can cause central nervous system toxicity with metronidazole. Other drugs such as phenytoin and warfarin can increase serum levels of disulfiram.
Treatment of Alcohol Abuse with Naloxone (ReVia)

Effects: Blocks alcohol craving May help prevent relapses Contraindications: Patients receiving opioids or in acute opioid withdrawal, history of sensitivity to naltrexone, naloxone or nalmefene, acute hepatitis or hepatic failure Dosing Options: 50 mg daily 100 mg QOD 150 mg q3 days Adverse Drug Reactions: Hepatotoxicity, N & V, headache Drug-Drug Interactions: Blocks the effects of opioid analgesia Monitoring: Liver function tests (LFTs), signs & symptoms of hepatotoxicity (e.g., jaundice, malaise) Naltrexone blocks the craving for alcohol and the reinforcing effects of alcohol consumption. Although it may help prevent relapses to alcoholism, it is contraindicated in patients with acute hepatitis or hepatic failure. Also, since naltrexone antagonizes the effects of narcotics, it can cause opioid withdrawal symptoms in patients receiving routine narcotic therapy for pain management. Naltrexone may be dosed at fifty milligrams per day, one hundred milligrams every other day, or one hundred fifty milligrams every three days. Adverse effects of naltrexone include those shown, with nausea being most common. Patients treated for alcoholism with naltrexone should be monitored using liver function tests and assessed for signs and symptoms of hepatotoxicity.
Treatment of Alcohol Abuse with Acamprosate (Campral)

Effects: Exerts effect via interaction with GABA and the glutamate system Reduces anxiety and enhances likelihood of maintaining absence Contraindications: Severe renal impairment Dosing: 666 mg TID and should be continued for 1 year despite relapsing Adverse Drug Reactions: Diarrhea and nausea Monitoring: Baseline labs should include serum creatinine (SrCr) Acamprosate is used to maintain sobriety and prevent the relapse of alcoholism. Although the exact mechanism is unknown, acamprosate is believed to exert its effect through GABA and the glutamate system, thus reducing unpleasant feelings of anxiety and prevent the urge to initiate drinking. Acamprosate therapy should continue for one year and should be continued even if the patient should relapse back to drinking alcohol. Typical dosing is 666 mg three times a day. This drug is contraindicated in patients with severe renal disease (SrCR less than 30 ml/min). In clinical trials, acamprosate was found to be more effective than placebo in maintaining abstinence and found naltrexone to be equally effective in maintaining abstinence. There has been no benefit shown in combining acamprosate with naltrexone in maintaining abstinence.
Alcohol-Drug Interactions
Alcohol induces hepatic metabolic enzymes, causing: Increased clearance of concurrent drugs Decreased serum drug levels Therapeutic failure Possible death
Alcohol and drug interactions can profoundly influence the effectiveness of medications which are taken concurrently. Alcohol induces hepatic metabolic enzymes, which causes the increased clearance of some drugs and may result in decreased serum levels of medications that share metabolic pathways. Therapeutic failure may result as well. When alcohol is mixed with prescription medications, such as barbiturates, benzodiazepines, narcotics, and other medications, the results may be fatal.

For additional information, see: Adams, W. L. & Cox, N. S. (1995). Epidemiology of problem drinking among elderly people. Int J Addict; 30(13-14): 1693-1716. Adams WL, Barry KL, Fleming MF (1996). Screening for problem drinking in older primary care patients. JAMA. 276:1964-1967. American Psychiatric Association. (1995). Practice guideline for the treatment of patients with substance use disorders: alcohol, cocaine, opioids. Am J Psychiatry. 152(11 Suppl): 1-59. Barrick C, Connors GJ. (2002). Relapse prevention and maintaining abstinence in older adults with alcohol-use disorders. Drugs Aging. 19(8): 583-94. Beers, M.H & Berkow, R. (2000). Substance Abuse and Dependence. The Merck Manual of Geriatrics. 3nd edition Section 4, Psychiatric Disorders. Whitehouse Station, NJ: Merck Research Laboratories: 333-342. Blow FC,Brower KJ, Schulenberg JE, et al. (1992). The Michigan Alcoholism Screening Test Geriatric Version (MAST-G): a new elderly specific screening instrument (abstract). Alcohol Clin Exp Res. 16:372. Buchsbaum, D. G., et al. (1992). Screening for drinking disorders in the elderly using the CAGE questionnaire. J Am Geriatr Soc; 40(7):662-665. Carlen, P. L., et al. (1994). Alcohol-related dementia in the institutionalized elderly. Alcohol Clin Exp Res; 18(6):1330-1334. DeHart, S. S. & Hoffmann, N. G. (1995). Screening and diagnosis of "alcohol abuse and dependence" in older adults. Int J Addict; 30(13-14):1717-1747.

Dufour, M. & Fuller, R. K. (1995). Alcohol in the elderly. Annu Rev Med; 46:123-132. Fink, A., Hays, R. D., Moore, A. A., & Beck, J. C. (1996). Alcohol-related problems in older persons. Determinants, consequences, and screening. Arch Intern Med; 156(11):1150-1156. Goldstein,M. D. Z., Pataki,A., & Webb, M. T. (1996). Alcoholism among elderly persons. Psychiatr Serv; 47(9):941-943. Joseph, C. L. (1995). Alcohol and drug misuse in the nursing home. Int J Addict; 30(13-14):1953-1984. Lakhani, N. (1997). Alcohol use amongst community-dwelling elderly people: a review of the literature. J Adv Nurs; 25(6):1227-1232. Liberto, J. G. & Oslin, D. W. (1995). Early versus late onset of alcoholism in the elderly. Int J Addict; 30(13-14):1799-1818. McCracken, A. L. (1998). Aging and alcohol. J Gerontol Nurs; 24(4):37-43. Oslin, D., Atkinson, R. M., Smith, D. M., & Hendrie, H. (1998). Alcohol related dementia: proposed clinical criteria. Int J Geriatr Psychiatry;13(4):203-212. Reid, M. C. & Anderson, P. A. (1997). Geriatric substance use disorders. Med Clin North Am; 81(4):999-1016. Saitz R, O'Malley SS. (1997). Pharmacotherapies for alcohol abuse. Withdrawal and treatment. Med Clin North Am. 81(4): 881-907. Smith,J. W. (1995). Medical manifestations of alcoholism in the elderly. Int J Addict; 30(13-14):1749-1798. Alcoholics Anonymous National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Sleep Disorders
By the end of this review concept, you will be able to: Describe typical age-related changes in the sleep cycle. Describe the epidemiology of sleep disorders in the elderly population. Differentiate transient and chronic sleep disorders. Differentiate primary and secondary sleep disorders. List common primary sleep disorders. List psychiatric, medical and pharmacological causes of secondary sleep disorders. Describe procedures for assessing and diagnosing sleep disorders in the elderly. Describe nonpharmacological therapies for the treatment of insomnia. Describe pharmacological options for the treatment of insomnia. Describe effects, dosing, side effects and contraindications for common agents used in the treatment of insomnia in the elderly. Describe pharmacological and nonpharmacological options for the treatment of apnea and other sleep disorders.
The Sleep Cycle and Age-Related Changes

Sleep Physiology Review
Stage 1 Period between sleep and wakefulness Initiates sleep Stage 2 Light sleep Muscle and brain activity shutdown Stage 3 Deep sleep 5% of total sleep time Occurs 1 to 3 hours after falling asleep Rebuilding stage for body Lessens with age Stage 4 Deep sleep 10 15% of total sleep time Rebuilding stage for body Lessens with age
REM Rapid eye movement stage Occurs in 90 minute cycles Longer during first half of sleep time Characterized by: Irregular breathing Increased heart rate Increased blood pressure Decreased core body temperature Decreased muscle tone Associated with dreaming
From: Neubauer DN. Sleep problems in the elderly. Amer Fam Phys. 1999;59(9):2551.
Agings Influence on Sleep More time spent in bed More time trying to fall asleep Less time sleeping Sleep tends to be lighter Stages 3 and 4 and REM sleep decreases More frequent awakenings Less time for restorative functions
The most deep sleep an average adjult gets is within the first 4 hours of falling asleep. The longer one sleeps, the less deep sleep that occurs and the more REM sleep that is experienced. As adults get older, they experience a number of changes in their sleep patterns. They tend to go to bed earlier, spending more time in bed trying to fall asleep and less time sleeping. Their sleep tends to be lighter, as stages three and four, and REM sleep decreases, as illustrated on the comparison graph of young adults sleep cycles compared with that of the elderly. This means that less time is spent in restorative sleep, and the person frequently awakens without feeling rested. While these changes result in more fragmented sleep, they are more or a less a natural consequence of the aging process.
Prevalence of Sleep Disorders in the Elderly

66% of residents in Long Term Care Facilities (LTCF) 23 34% of geriatric population
When these changes in sleep patterns threaten the health and well being of the individual, the person is said to have a sleep disorder. Up to 66% of residents in long-term care facilities have some type of sleep disturbance related to a primary sleep disorder, a mental or medical condition, or substance abuse. In the general geriatric population, 23 to 34% of older adults report symptoms of insomnia, such as difficulty falling and staying asleep, and early morning awakenings. Untreated and severe insomnia may lead to increased mortality.
Types of Sleep Disorders

Transient: Lasts 2 to 3 days Short-term: Lasts days to weeks, but less than 3 weeks Associated with an acute stressor Chronic: Lasts > 3 weeks Caused by one or more contributing factor(s) History of sleep problems
Insomnia may be either transient, lasting only a couple of days; short-term, lasting several days to weeks; or, chronic. Sleep disorders are generally considered chronic if they persist longer than three weeks. Transient and short-term insomnia is usually associated with an acute stressor, such as jet lag or work-related stress, whereas chronic insomnia is typically caused by one or more long-term contributing factors, such as a medical condition.
Etiology of Sleep Disorders

Primary: Dyssomnias (insomnia) Hypersomnias (excessive sleepiness) Parasomnias (abnormal behaviors during sleep) Secondary: Mental disorder Medical condition Medications Substance abuse
Audio Transcript Primary sleep disorders include dyssomnias, hypersomnias, and parasomnias. Secondary sleep disorders may be caused by other psychiatric disorders, medical conditions, medications, and/or substances of abuse.
Primary Sleep Disorders

Dyssomnias: Primary insomnia Narcolepsy (rare) Breathing-related disorder (sleep apnea): Central sleep apnea Obstructive sleep apnea Mixed apnea Circadian-rhythm disorder Restless leg syndrome
Dyssomnias are disorders in initiating or maintaining sleep, or of excessive sleepiness. They include primary insomnia that is not secondary to another disorder or use of drugs, and narcolepsy, which is rather infrequent in the elderly. Dyssomnias also include breathing-related disorders such as sleep apnea. The three patterns of apnea include central sleep apnea, obstructive sleep apnea, and mixed apnea. Apneas may be lethal if associated with hypoxemia and cardiac arrhythmias. They also contribute to sudden nocturnal death in the early morning hours. Circadian-rhythm disorder is another type of dyssomnia that involves changes in the duration of circadian cycles with age. Such changes can affect other homeostatic rhythms and reduce total sleep time. Other dyssomnias include restless leg syndrome, which can cause repeated awakenings.

Hypersomnias: Sleep apnea Narcolepsy Kleine-Levin Syndrome Nocturnal myoclonus
Hypersomnias are a more severe problem than insomnia. Sleep apnea, as mentioned before, is characterized by cessation of breathing for about 10 seconds for at least 30 episodes during the night. Narcolepsy consists of a tetrad of symptoms. One of these symptoms is sudden, brief (approximately 15 minutes) sleep attacks that can occur during any type of activity. Another symptom is cataplexy, or sudden loss of muscle tone that may cause the patient to slump to the floor, unable to move. A third symptom is sleep paralysis, characterized by a generalized flaccidity of muscles with full consciousness in the transition zone between sleep and walking. The fourth symptom of narcolepsy is hypnagogic hallucinationsvisual or auditorywhich may precede sleep or occur during the sleep attack. The attacks are characterized by an abrupt transition into REM sleep, a necessary criterion for diagnosis. Kleine-Levin syndrome predominates in young men and is characterized by hypersomnic attacks three or four times a year. These attacks can last up to 2 days, and typically are associated with hyperphagia, hypersexuality, and mental status changes upon awakening. This syndrome typically remits after the age of 40. Nocturnal myoclonus is characterized by periodic lower leg movements that occur during sleep with subsequent daytime sleepiness, anxiety, depression, and cognitive impairment.

Parasomnias: Pavor nocturnes (sleep terror) Nightmare disorder Somnambulism Enuresis
Parasomnias typically begin in childhood and resolve with age. Sleep terror tends to affect preadolescents, but can also affect adults, and is characterized by an abrupt awakening from stage 3 or 4 sleep. Symptoms include: fear, sweating, tachycardia, and confusion for several minutes, with amnesia for the event. Nightmares may occur during REM sleep. Sleepwalking, or somnambulism, includes ambulation or other fine behaviors while still asleep, and again with amnesia for the event. Sleepwalking in the elderly (as it predominates in children), can be a feature of dementia. Enuresis is involuntary micturition during sleep in a person who has voluntary control while awake. Again, this parasomnia predominiates in children and this section is included for complete review of sleep disorders.
Secondary Sleep Disorders

Psychiatric Conditions: Depression Anxiety Psychosis Medical Conditions: Parkinsons disease Dementia Pulmonary disease Endocrine disorders Arthritis Acute and chronic pain Nocturia Substances: Medications Substances of abuse
Secondary insomnia in the elderly is commonly due to general mental conditions that disrupt sleep and increase sleep latency and early morning awakenings. Depression, anxiety, and psychosis are examples of such conditions. Medical illnesses that can induce insomnia include: Parkinsons disease, dementia, pulmonary disease, and pain. Finally, substance use and abuse can influence sleep disturbances in the elderly.
Medications That May Cause Secondary Sleep Disorders

Table: Medications Contributing to Secondary Sleep Disorders Alcohol / Alcohol withdrawal Appetite suppressants Amantadine Benzodiazepine withdrawal Bupropion Caffeine Clonidine Corticosteroids CNS stimulants Decongestants Levodopa Lithium MAOIs Methyldopa Nicotine (use and withdrawal) Propranolol Selegiline SSRIs Diuretics
Drugs that contribute to the development of insomnia are listed on your screen. Although alcohol initially causes drowsiness, it disrupts sleep later in the evening, decreases REM sleep, and increases awakenings.
Signs and Symptoms of Sleep Disorders

Excessive daytime somnolence Unrefreshing sleep Napping in the day Insomnia at night
The elderly who complain about insomnia generally admit to excessive daytime sleepiness and unrefreshing sleep. Again, this is due to the fact that restorative sleep in stage 3 and 4 is reduced. As a result, patients will tend to nap more in the day, which contributes to the vicious cycle of increased sleep latency at bedtime. If left untreated, this sleep deficit can lead to cognitive impairment, resulting in a greater risk of accidents and falls, and an inability to carry out daily tasks.
Diagnosing Sleep Disorders

Obtain medical and psychiatric history Document sleep habits Duration of sleep Type of sleep problem Signs/symptoms of sleep problem(s) & duration Daily function & alertness Complete physical exam Laboratory workup Thyroid function studies ECG Chest x-ray Pulmonary function tests Determine conditions which disrupt sleep Check nocturnal wheezing Check repetitive stereotypic leg movements If apnea, refer for polysomnography
To diagnose insomnia, a complete medical and psychiatric history should be obtained. Sleep habits of the patient should be documented every twenty-four hours for several days to weeks. Long-term care staff, the patient, or family caregivers can keep a sleep diary of the patients sleeping habits. The diary should note the duration of sleep, type of sleep problem(s), daily functioning, and level of daytime alertness. The diary should reveal signs and symptoms of a major primary sleep disorder, and their duration. A complete physical exam should be conducted, and lab tests assessed for occult conditions that may be contributors. All medical conditions and treatment that disrupt sleep should be ruled out. Besides observation, occurrence of nocturnal wheezing and repetitive stereotypic leg movements should be noted. If apnea is likely, polysomnography should be ordered.
Nonpharmacological Treatment of Sleep Disorders

Discontinue/replace offending drugs Optimize treatment of chronic diseases Establish hygienic sleep practices Comfortable environment Regular schedule Relaxation techniques Avoid stimulating substances, and alcohol Avoid routine use of hypnotics Limit day naps Restrict bedtime fluids Treat specific primary sleep disorders (e.g., obstructive sleep apnea) Weight loss Avoid alcohol and sedative-hypnotics Mechanical and surgical measures Continuous positive airway pressure (CPAP) Monitor therapeutic responses
If a secondary sleep disorder is highly suspected, the clinician should consider discontinuing any offending drugs and substituting less problematic alternatives. The clinician should also take steps to optimize treatment of chronic diseases known to disrupt sleep. Establishing consistent sleep hygiene practices, such as those listed here, can help alleviate the disorder. Patients with obstructive sleep apnea should lose weight if necessary, and avoid alcohol and sedative-hypnotics. If the patient does not respond to treatment, mechanical and surgical measures can be taken such as nasal continuous positive airway pressure, or in extremely severe cases a tracheotomy may need to be performed. It is essential to monitor all therapeutic responses to these treatment measures.
Cognitive Behavior Therapy

1. Go to bed only when sleepy 2. Use the bed and bedroom only for sleep and intimacy (e.g.,: no reading, TV watching, or worrying in bed or the bedroom during the daytime or at night) 3. Get out of bed and go to another room when unable to fall asleep within 15 to 20 minutes 4. Repeat step 3 as often as necessary, either when trying to fall asleep or to get back to sleep 5. Arise at the same time every morning, regardless of the amount of sleep obtained the previous night
In a study published in JAMA in 1999, subjects receiving cognitive-behavior therapy attended 8 weekly 90-minute therapy sessions conducted in small groups of 4 to 6 individuals. Treatment consisted of a structured, multifaceted intervention involving behavioral, cognitive, and educational components that targeted different facets of late-life insomnia. The behavioral component used sleep restriction therapy and stimulus control procedures. Sleep restriction consisted of curtailing time in bed to the actual sleep time, like step 2 on your screen. Daytime napping was made optional during this study, as long as it was limited to less than 1 hour and prior to 3:00 PM. Overall, behavioral interventions into sleep hygiene had the most sustained effect over the 2 years of the study.
Cognitive Behavior Therapy vs. Pharmacotherapy
From: Morin CM, et al. Behavioral and Pharmacological Therapies for Late-Life Insomnia: A Randomized Controlled Trial. JAMA. 1999;281:991-999.
The figure on the left side of your screen is a post hoc comparison showing subjects in the cognitive-behavior therapy group and combined conditions rating themselves as significantly more improved and less impaired than subjects in either the pharmacotherapy or placebo groups. The bar graph on the right of your screen shows changes in wake after sleep onset (WASO), as measured by patients sleep diaries. For the cognitive-behavior therapy condition, there was no significant change on any of the dependent variables at any follow-up, suggesting that treatment gains achieved by post-treatment assessment were well maintained. The pharmacotherapy intervention showed significant worsening from the post-treatment period, especially noted at the 24-month follow-up, for total wake time, sleep efficiency, and wake after sleep onset. For the combined interventions, statistically significant changes were obtained at all 3 follow-up periods (3, 12, and 24 months) on measures of total wake time, sleep efficiency, and wake after sleep onset, which may indicate significant worsening of sleep pattern over time.
Pharmacological Treatment of Sleep Disorders: Agents

Benzodiazepines (e.g., triazolam, temazepam, others) Chloral hydrate Antihistamines (e.g., diphenhydramine) Nonbenzodiazepines (e.g., zolpidem, zaleplon, eszopiclone) TCAs (e.g., imipramine, others) Mirtazipine Trazodone Ramelteon **Note: Dosages for many of these must be adjusted for elderly patients
The medication classes listed on your screen have replaced barbiturates as preferred hypnotic agents because of their greater safety profile in overdose situations and their reduced effects on hepatic enzyme induction. Today, hypnotic sedatives such as benzodiazepines and nonbenzodiazepines are often prescribed for insomnia, particularly in the community-dwelling elderly. However, these drugs also have their drawbacks. In addition to being the largest underrecognized cause of hypersomnolence, long-term use of agents such as benzodiazepines and tricyclic antidepressants often causes adverse effects and is associated with morbidity incurred with falls. Sedating antidepressants, such as mirtazipine, are also used for dual treatment of insomnia, depression, and/or appetite stimulation. In general, it is generally appropriate to use medications for short courses of 1 2 weeks.
Treatment of Insomnia with Benzodiazepines

Mechanism of Action: Induce sleep Decrease sleep latency and nocturnal awakenings Suppress stages 3, 4, and REM sleep Agents: Short-acting Triazolam (Halcion) Intermediate-acting Temazepam (Restoril) Estazolam (ProSom) Quazepam (Doral) Long-acting (not recommended in elderly) Flurazepam (Dalmane) Diazepam (Valium) Chlordiazepoxide (Librium) Disadvantages: Adverse Drug Reactions: Impaired coordination, daytime sedation, cognitive impairment, dizziness, anterograde amnesia, increased falls Contraindications: Patients with sleep apnea
Treatment of Insomnia with Benzodiazepines
Benzodiazepines are still the most widely prescribed medication for insomnia. The shorter acting agents induce sleep and decrease sleep latency, and all benzodiazepines suppress stages three, four, and REM sleep. Benzodiazepines include short- and intermediate-acting agents such as triazolam and temazepam. Long-acting agents such as flurazepam, diazepam, and chlordiazepoxide form active metabolites and should not be used in the elderly due their greatly prolonged elimination half-lives. These agents have also been associated with cognitive impairment and increased risk of hip fractures. All benzodiazepines are associated with similar adverse effects such as impaired motor coordination, daytime sedation with cognitive impairment, and dizziness. Because they decrease respiratory drive and worsen obstructive breathing disorders, all benzodiazepines are contraindicated in the treatment of sleep apnea. The use of benzodiazepines needs to be closely monitored to ensure appropriateness of indication, dose, and duration, especially when using unnecessary and potentially hazardous agents as defined in the Health Care Financing Administration guidelines.
Treatment of Insomnia with Short-Acting Benzodiazepines

Triazolam Dosing 0.125 mg qHS Adverse Drug Reactions: Rebound insomnia Daytime anxiety Amnesia
Triazolam, a short-acting benzodiazepine, does not have active metabolites, and is helpful in reducing sleep latency. However, rebound insomnia and amnesia may result, especially at higher doses. The usual geriatric starting dose is 0.125 mg and should only be used for very short periods of time because of its increased association with dependency, transient psychotic reactions, and rebound anxiety.
Treatment of Insomnia with Intermediate-acting Benzodiazepines

Temazepam (preferred in older adults) Maintains sleep with fewer residual effects Starting dose is usually 7.5 mg qHS Take 60 90 minutes before bedtime Estazolam Starting dose is usually 0.5 mg qHS Daytime sedation can occur Take 60 90 minutes before bedtime Quazepam Starting dose is usually 7.5 mg qHS Daytime sedation is common Parent compound: 25 53 hour half-life Active metabolites: 40 190 hour half-life Take 60 90 minutes before bedtime
Temazepam, estazolam, and quazepam are intermediate-acting benzodiazepines. These agents are useful for sleep maintenance, and should be taken an hour to an hour and a half before bedtime. Because they form no active metabolites, temazepam and estazolam improve sleep maintenance without causing significant daytime residual effects and may be preferred in the elderly. Quazepam is metabolized to at least one active metabolite with a potential half-life up to 8 days and should be avoided in the elderly population.
Treatment of Insomnia with Chloral Hydrate

Chloral Hydrate Advantages: Rapid onset Adverse Drug Reactions: Gastric irritation Next day hangover Contraindications: Moderate to severe renal failure Hepatic dysfunction Drug Interaction concerns: May increase the effect of warfarin May increase CNS depression if taken concurrently with ethanol CYP2E1 substrate **Not recommended for elderly! Chloral hydrate has a peak effect within 30 60 minutes and only a 4 8 hour duration, but is not recommended for use in the elderly whatsoever. Side effects include gastric irritation and next-day hangover. Other drawbacks of chloral hydrate include the rapid development of tolerance and drug-drug interactions. This agent is contraindicated in the elderly with moderate to severe renal failure and hepatic dysfunction. However, chloral hydrate is available in liquid form for patients with difficulty swallowing. Also, chloral hydrate can be used for procedural sedation, and is generally its only use in todays practice.
Treatment of Insomnia with Antihistamines (e.g.: Diphenhydramine)

Advantages: Induce sleep Improve sleep maintenance Available in prescription and nonprescription forms Adverse Drug Reactions: Significant anticholinergic effects: confusion, dizziness, urinary Contraindications: Dementia, prostatic hypertrophy, glaucoma, chronic constipation **Not recommended for elderly!
retention, decreased alertness
Antihistamines like diphenhydramine induce sleep with a low sedative potency. Disadvantages of antihistamines include the quick development of tolerance and significant anticholinergic side effects. Consensus panel recommendations from experts on geriatric prescribing suggest that antihistamines not be utilized in the older adult, and are contraindicated for patients with dementia, prostatic hypertrophy, glaucoma, and chronic constipation due to their potent anticholinergic properties. This also correlates with restrictions placed on antihistamine use in the elderly by the Health Care Financing Administration (HCFA). Antihistamines, including diphenhydramine, chlorpheniramine, and brompheniramine, are in a large number of both combination and non-combination products available direct to the consumer over-the-counter. It is important to recognize these agents and counsel patients with regard to their potential harm.
Treatment of Insomnia with Nonbenzodiazepines

Advantages: Effective at reducing sleep latency Rapid onset of action Short half-life (increased in elderly and those with hepatic dysfunction) Preserves stages 3 and 4 sleep Little or no rebound tolerance Agents and Dosing: Zolpidem (Ambien) Member of the imidazopyridine class Half-life is 2 3 hours, up to 10 hours in patients with moderate to severe liver dysfunction Effective for short-term treatment of transient insomnia Start at 5 mg qHS, immediately before bedtime May repeat dose if desired wake time is greater than 4 hours from time sleep is interrupted Zolpidem controlled release (Ambien CR) Biphasic absorption Immediate release and controlled release halves Food increases Tmax to 4 hours and decreases Cmax by 30% Showed decreased wake after sleep onset (WASO) for first 7 hours during the first 2 nights, and for first 5 hours after 2 weeks of therapy Polysomnography showed increased wakefulness at the end of the night compared to placebo-treated patients No significant decrease in performance 8 hours after taking a dose Next day somnolence was 15% versus 2% for placebo In two placebo-controlled trials, rebound insomnia was seen only on the first night after abrupt discontinuation, but not on the second night
FROM: Ambien CR Package Insert.
Zaleplon (Sonata) Member of the pyrazolopyrimidine class Half-life is about 1 hour Start at 5 10 mg qHS, immediately before bedtime May repeat dose if desired wake time is greater than 4 hours from time sleep is interrupted Minimal residual daytime effects Avoid giving near / with high fat foods Delayed time to maximum concentration by up to 2 hours Reduced maximum concentration by up to 35%

Eszopiclone (Lunesta) S-enantionmer (active isomer) of the racemic mixture zolpiclone Eszopiclone has a 50 times greater binding affinity for the benzodiazepine receptor than zopiclone Cyclopyrrolone derivative Decreases sleep latency, improves sleep maintenance Rapid absorption Slowed by high fat, heavy metal meals Reaches peak absorption in 1 hour Elimination half-life ~6 hours Hepatic and renal metabolism CYP3A4, 2E1 75% primary metabolites renally eliminated Starting dose is generally 2 mg qHS 1 mg if given with strong 3A4 inhibitor(s) 1 mg preferred starting dose in elderly Dose reduction necessary in all stages of hepatic dysfunction Max dose is 3 mg Approved for continuous, long-term use Zammit, et al. Curr Med Res Opin. 2004;20(12):1979-1991. Adverse Drug Reactions: Headache, lightheadedness or dizziness, somnolence, coordination difficulties, GI upset, possible hallucinations Contraindications: Sleep apnea

Zolpidem, zaleplon, and eszopiclone are from the newer class of hypnotics classified as non-benzodiazepines. Nonbenzodiazepines have preferential binding when compared to the benzodiazepine subtype, and this specificity provides better tolerability than the benzodiazepines. These non-benzodiazepines are effective in increasing stages 3 and 4 sleep, and are also effective at reducing sleep latency. All three agents have a rapid onset of action and a short half-life, which is increased in the older adult and in those with hepatic dysfunction. Controlled-release zolpidem is designed to help with falling asleep and staying asleep, eliminating the potential for a possible need of repeating the dose if awakening after sleep onset occurs. Eszopiclone had a year-long study that showed its continued efficacy and lack of tolerance development or withdrawal symptoms when discontinued after a year of continuous use. The adverse effects listed on your screen are typically dose-related. Neuropsychiatric effects such as hallucinations have also been noted in the elderly. Also, take note of the reduced concentration levels of zaleplon and eszopiclone if given with or near fatty food intake. And remember, zolpidem and zaleplon are not recommended for continuous use and are typically recommended for durations of not more than 10 to 14 days at a time, or 21 days in a 30 day period.
Treatment of Insomnia with TCAs

Treatment with Tricyclic Antidepressants Generally not recommended in elderly Adverse effects: Anticholinergic side effects Orthostatic hypotension Cardiac-conduction effects Daytime sedation
Sedating antidepressants are effective for insomnia caused by depression, an example of treating the cause rather than the symptom. However, the tricyclic antidepressants are not preferred therapy in the elderly due to their anticholinergic side effects, orthostatic hypotension, cardiac-conduction effects, and daytime sedation.
Treatment of Insomnia with Trazodone

Trazodone Advantages: May be beneficial if concomitant depression is present One of the preferred options for chronic insomnia when used at lower doses Dose: 25 100 mg qHS (generally lower than antidepressant dosage) Adverse effects: Few anticholinergic effects Orthostatic hypotension Peripheral edema Daytime sedation at excessive doses In contrast, trazodone, with a more tolerable adverse effect profile, may be utilized in the treatment of chronic insomnia at lower doses than commonly used in the treatment of depression. Priapism is a rare but serious side effect requiring emergent treatment.
Treatment of Insomnia with Ramelteon

Ramelteon (Rozerem) Melatonin receptor agonist Affinity for MT1 and MT2, not MT3 Acts on brains circadian control center No potential for abuse / dependence Suitable for long-term use Dosing 8 mg 30 minutes prior to bedtime High-fat meals decrease bioavailability and delay absorption Contraindications Severe hepatic impairment or in combination with fluvoxamine (1A2 inhibitor) Metabolized by CYP450 1A2 Some 2C subfamily and 3A4 isoenzyme activity
The first hypnotic agent with a new mechanism of action approved in over 35 years, ramelteon is a melatonin receptor agonist with a high affinity for melatonin MT1 and MT2 receptors over the MT3 receptor. Endogenous melatonin acts on MT1 and MT2 receptors, which is thought to contribute to ramelteons sleep promoting properties. Ramelteon is designed for use in accordance with the maintenance of the circadian rhythm underlying the sleep-wake cycle. The major metabolite, MII [M-two], is active with approximately one-tenth to one-fifth the binding affinity of the parent molecule for the MT1 and MT2 receptors, respectively, and is 17- to 25-fold less potent in in vitro functional assays. However, MII circulates at higher concentrations than the parent compound, producing a 20- to 100-fold mean systemic exposure when compared to ramelteon. The metabolite also has a slight affinity for the serotonin 5-HT2B receptor.
Restless Leg Syndrome

Diagnosis Patients experience urge to move the legs Often associated with paresthesias / dysesthesias deep within the legs Paresthesias / dysesthesias and urge to move are worse or exclusively present during periods of rest or inactivity Relieved, at least temporarily, by activity Symptoms show a circadian rhythm, being worse in the late evening or at night, and less severe or absent during the day
FROM: Montplaisir J, et al. Movement Disorders. 2006;21(10):1627-1635.
Treatment Ropinirole (Requip) (currently only FDA-approved option) Carbamazepine Levodopa Clonazepam Bromocriptine Narcotic analgesics
FROM: Montplaisir J, et al. Movement Disorders. 2006;21(10):1627-1635.
Restless Leg Syndrome

Restless leg syndrome, or Ekbom syndrome, is a chronic neurological movement disorder. Ropinirole recently gained approval for the indication of the treatment of RLS. Table 2 from the Montplaisir, et al. study illustrates data indicating that all patients experienced decreases in sleep disturbances and somnolence, as well as improvements in sleep quanitity and adequacy during ropinirole treatment during the single-blind treatment phase of the study. Carbamazepine, levodopa, clonazepam, bromocriptine, or narcotic analgesics may be considered for those refractory or intolerant to ropinirole.
Treatment of Other Sleep Disorders

Obstructive Sleep Apnea: Continuous positive airway pressure (CPAP) or biphasic positive airway pressure (BiPAP) Severe Sleep Apnea: CPAP or otolaryngologic surgery (not appropriate for dementia patients) Nocturnal Myoclonus: Benzodiazepines (e.g., clonazepam)
For obstructive sleep apnea, continuous positive airway pressure, or CPAP, is the current treatment of choice. CPAP is effective in increasing oxygenation, consolidating sleep, and improving daytime cognition and alertness. Biphasic positive airway pressure may be used for patients intolerant or having incomplete satisfaction with CPAP treatment. BiPAP can decrease respiratory exertion on the patient, allowing the patient to exhale more easily by having a reduced pressure to expire against. Treatment for severe sleep apnea includes continuous positive airway pressure and otolaryngologic surgery. Nocturnal myoclonus may improve with benzodiazepines such as clonazepam; however, geriatric patients should be monitored closely for adverse effects. There is currently no approved treatment for Kleine-Levin syndrome.
References & Resources

For additional information, see: Agostini J, Leo-Summers L, Inouye SK. Cognitive and other adverse effects of diphenhydramine use in hospitalized older patients. Arch Int Med. 2001;161:2091-2097. Ambien (zolpidem) [Package Insert]. New York: Sanofi-Synthelabo Inc.; Mar 2004. Bixler EO, et al. Effects of age on sleep apnea in men. Am J Respir Crit Care Med. 1998;157:144-148. Cadieux RJ. Geriatric psychopharmacology. A primary care challenge. Postgrad Med. 1993;93(4):281-282, 285-288, 294-301. Caples SM, Gami AS, Somers VK. Obstructive sleep apnea. Ann Int Med. 2005;142:187-197. Coope J. Hormonal and non-hormonal interventions for menopausal symptoms. Maturitas. 1996;23(2):159-168. Erman et al. An efficacy, safety, and dose-response study of ramelteon in patients with chronic primary insomnia. Sleep Medicine. 2006;7:17-24. Flamer HE. Sleep problems. Med J Austral. 1995;162(11):603-607. Grad RM. Benzodiazepines for insomnia in community-dwelling elderly: a review of benefit and risk. J Fam Pract. 1995;41(5):473-481. Haponik EF. (1994). Sleep problems. In: Hazzard WR, et al, (Eds.). Principles of Geriatric Medicine and Gerontology, 3rd ed. New York: McGraw-Hill, 1213-1227.

Hoehns JD & Perry PJ. Zolpidem: a nonbenzodiazepine hypnotic for treatment of insomnia. Clin Pharm. 1993;12:814-828. Inouye SK, et al. The role of adherence on the effectiveness of nonpharmacologic interventions. Arch Int Med. 2003;163:958-964. Jacobs GD, et al. Cognitive behavior therapy and pharmacotherapy for insomnia. Arch Int Med. 2004;164:1888-1896. JAMA. Patient Page. 1999;281: 1056. Klett CJ. Review of triazolam data. J Clin Psychiatry. 1992;53(Suppl):61-68. Krystal et al. Sustained efficacy of eszopiclone over 6 months of nightly treatment: result of a randomized, double-blind, placebo-controlled study in adults with chronic insomnia. Sleep. 2003; 26:793-799. Lasagna L. Over-the-counter hypnotics and chronic insomnia in the elderly. J Clin Psychopharmacology. 1995;15(6): 383-386. Lavie P. Sleep disturbances in the wake of traumatic events. NEJM. 2001;345(25):1825-1832. Lunesta (eszopiclone) [Package Insert]. Marlborough, MA: Sepracor Inc.; Feb 2005. Marshall LL & Miller SW. Sleep Disorders with Aging. ASCP Clinical Consult, Supplement 8, 1996. http://www.ascp.com/public/pubs/cc/supp8.shtml

McCall WV. Management of primary sleep disorders among elderly persons. Psychiatr Serv. 1995;46(1):49-55. Monane M. Insomnia in the elderly. J Clin Psychiatry. 1992;53(suppl):23-28. Montplaisir J, Karrasch J, Haan J, Volc D. Ropinirole is effective in the long-term management of restless leg syndrome: a randomized controlled trial. Movement Disorders. 2006;21(10):1627-1635. Morin CM et al. Behavioral and pharmacological therapies for late-life insomnia: a randomized controlled trial. JAMA. 1999;281:991-999. Neubauer DN. Sleep problems in the elderly. Amer Fam Phys. 1999;59(9):2551. Ohayon MM. Prevalence and correlates of nonrestorative sleep complaints. Arch Int Med. 2005;165:35-41. Roth et al. Ramelteon (TAK-375), a selective MT1/MT2 receptor agonist, reduces latency to persistent sleep in model transient insomnia related to a novel sleep environment. Sleep. 2005;28(3):303-307. Rozerem (Ramelteon) [Package Insert]. Lincolnshire, IL: Takeda Pharmaceuticals America, Inc.; Aug 2005. Salva P & Costa J. Clinical pharmacokinetics and pharmacodynamics of zolpidem: therapeutic implications. Clin Pharmacokin. 1995;29(3):142-153. Scharf MB, et al. Effectiveness of low-dose temazepam on sleep in geriatric insomniac subjects. Consult Pharm. 1993;8 (12):1367-1373.

Scharf MB, et al. Effects of buspirone and alprazolam on snoring and sleep apnea in geriatric patients. Consult Pharm. 1994;9(6):660-668. Schenck CH. Assessment and Management of Insomnia. JAMA. 2003 May 21;289(19):2475-2479. Shorr RI & Robin DW. Rational use of benzodiazepines in the elderly. Drugs Aging. 1994;4(1):9-20. Simon GE, et al. Prevalence, burden, and treatment of insomnia in primary care. Am J Psych. 1997;154:1417-1423. Siversten B, et al. Cognitive behavior therapy vs zopiclone for treatment of chronic primary insomnia in older adults: a randomized controlled trial. JAMA. 2006;295(24):2851-2858. Sonata (zaleplon) [Package Insert]. Bristol, TN: King Pharmaceuticals, Inc.; Jul 2003. Swift CG & Shapiro CM. ABC of sleep disorders: sleep and sleep problems in elderly people. Brit Med J. 1993;306 (6890):1468-1471. Trenkwalder C, et al. Ropinirole in the treatment of restless leg syndrome: results from the TREAT RLS 1 study, a 12 week, randomised, placebo controlled study in 10 European countries. J Neurol Neurosurg Psychiatry. 2004;75:92-97. Walsh JK, et al. Lack of residual sedation following middle-of-the-night zaleplon administration in sleep maintenance insomnia. Clinical Neuropharmacology. 2000;23(1):17-21. Walters AS, et al. Ropinirole is effective in the treatment of restless leg syndrome: TREAT RLS 2 a 12-week, doubleblind, randomized, parallel-group, placebo-controlled study. Movement Disorders. 2004;19:1414-1423.

Yoon IY et al. Age-Related Changes of Circadian rhythms and Sleep-Wake Cycles. JAGS. 2003;51:1085-1091. Zammit GK, et al, Efficacy and safety of eszopiclone across 6-weeks of treatment for primary insomnia. Current Medical Research and Opinion. 2004;20(12):1979-1991.
Psychoses
By the end of this review concept, you will be able to:
Describe the epidemiology ofpsychosis in the elderly. Differentiate between early-onset and late-onset schizophrenia List the signs and symptoms of schizophrenia and other psychotic disorders. Summarize guidelines for diagnosing psychotic disorders in the elderly. Differentiate between conventional and atypical antipsychotic medications used to treat psychosis in elderly patients. Summarize guidelines for the administration of antipsychotic therapy in the elderly. Describe mechanism of action, clinical benefits, dosing, adverse effects and monitoring protocols for conventional agents used to treat psychosis in elderly patients. Describe clinical presentation, management and monitoring guidelines associated with extrapyramidal effects of antipsychotic therapy. Describe mechanism of action, clinical benefits, dosing, adverse effects and monitoring protocols for atypicalagents used to treat psychosis in elderly patients. Describe pharmacokinetic and pharmacodynamic interactions associated with the use of antipsychotic therapy.
Epidemiology of Psychosis in the Elderly

Prevalence: Late-onset psychosis accounts for 10% of elderly psychiatric hospital admissions Primary psychotic disorders: Schizophrenia Schizoaffective disorder Delusional disorder Brief psychotic disorder Secondary psychotic disorders: Dementia with psychosis Parkinsons with psychosis Psychosis secondary to general medical conditions Psychosis secondary to substance use
Late-life psychosis is a common and pathologically heterogeneous disorder. The condition accounts for up to ten percent of psychiatric hospital admissions for patients over the age of sixty. Psychotic symptoms in the elderly can be classified into primary psychotic disorders, including schizophrenia and secondary psychotic disorders, for which psychotic symptoms are associated with dementias such as Alzheimers disease and medical conditions such as delirium.
Early-Onset vs. Late-Onset Schizophrenia

Early Onset Age of Onset Percentage of Cases Clinical Course Risk Factors < 40 years 15-33% stabilizes with age Late Onset > 50 years 5-14% worsens with age women > men
Schizophrenia is among the most expensive disorders in terms of treatment costs and need for public assistance. It is a chronic and severe psychiatric disorder with a lifetime prevalence of 1%. Onset of the illness typically begins in early adulthood. This type of schizophrenia is termed early onset schizophrenia, and those that develop it may stabilize and even symptomatically improve with age. A small, but distinct group experience their first onset of symptoms later in life. Late-onset schizophrenia presents after the age of forty-five. Persons with late-onset schizophrenia typically require lower doses than their early-onset counterparts. Late-onset schizophrenia affects more women than men.
Signs and Symptoms of Schizophrenia

Positive Symptoms: delusions illusions hallucinations Negative Symptoms: emotional flatness loss of drive or initiative limited speech loss of interest in life or pleasure Thought Disorder: confused thinking disorganized speech, behavior, and perceptions
Signs and symptoms of schizophrenia are commonly classified as positive, negative, and thought disorder. Positive symptoms include delusions and hallucinations, and generally respond better to pharmacotherapy than negative symptoms which include emotional flatness, limited speech and loss of initiative. Symptoms characteristic of thought disorder include confused thinking which is less severe with late onset schizophrenia, and disorganized speech, behavior and perceptions.
Psychotic Symptoms and Other Conditions

Delusional Disorder: nonbizarre delusions without hallucinations no cognitive impairment Dementia with Psychotic Features: Alzheimers disease psychosis associated with Parkinson's disease and treatment Affective Psychosis: depression with psychotic features manic phase of bipolar disorder Delirium (is reversible): medical illnesses medications Besides schizophrenia, psychotic symptoms play a prominent role in other psychiatric conditions frequently seen in the elderly. Delusional disorder is characterized by the presence of nonbizarre delusions that persist. The delusions typically involve situations that may occur in real life, such as being poisoned or having a disease. These patients are often cognitively intact women. Hearing and visual impairment seem to be risk factors. More than seventy-five percent of patients with Alzheimer's dementia will exhibit psychotic symptoms throughout the course of the disease. Patients with Parkinson's disease often experience psychosis as a consequence of dopaminergic drug therapy. Psychosis also may appear in conjunction with a mood disorder, such as depression. The elderly are very susceptible to developing delirium due to multiple medical comorbidities and multiple drug therapies. Delirium often produces psychotic symptoms that resolve after the underlying cause is addressed.
Diagnosing Psychosis
medical history physical examination laboratory tests - blood or urine samples
As with any new onset of psychiatric symptoms in the elderly, patients must be thoroughly evaluated to determine if the cause of their symptoms is reversible. Medical history, physical examination and laboratory tests can help rule out medical causes of psychotic symptoms.
Pharmacological Treatment of Psychosis

Overall Benefits: relief of symptoms improvement in level of functioning Conventional Antipsychotics: second line therapy for late life psychosis low, intermediate, high-potency agents effects mediated by D2 receptor blockade in the basal ganglia disabling ADRs - anticholinergic activity, extrapyramidal symptoms, tardive dyskinesia Atypical Antipsychotics: first line therapy for late life psychosis effective in treating negative schizophrenia symptoms adverse effects reduced expensive
Antipsychotic drugs are often utilized in the treatment of all types of psychotic disorders. These medications do not affect the course of the illness or treat the underlying cause, but they do provide symptomatic relief. Resolution of psychotic symptoms often greatly improves the patient's overall level of functioning. Conventional antipsychotic medications have been available since the 1950s and include low, intermediate, and high-potency agents. These antipsychotic agents are considered by many to be second line therapy for the treatment of late life psychosis due to their disabling adverse effects in the elderly population. Atypical antipsychotics, available since the 1990s, are more effective in treating negative symptoms of schizophrenia. Due to decreased incidence of significant adverse effects, atypical antipsychotics are preferred agents for the treatment of psychosis in the elderly population. However, the higher costs of these agents may be problematic.
Guidelines for Conventional and Atypical Antipsychotic Therapy in the Elderly

Start low and go slow Select agent least likely to exacerbate pre-existing conditions Increase dose at intervals no less than one week apart With sedating agents, administer largest portion of dose at bedtime Lower doses for dementia syndromes Re-evaluate every 6 months. Reduce dosage if stable Monitor: frequency and severity of psychotic symptoms ADRs (e.g., anticholinergic effects, constipation, urinary retention, confusion, orthostatic hypotension, episodic falling)
The general principles for treating the elderly with both conventional and atypical antipsychotics are listed on your screen. First, always start low and go slow. Select an agent that is least likely to exacerbate pre-existing conditions. For example, low potency agents are preferred over high potency agents for Parkinson's disease. Increase doses at intervals no less than one week apart. If utilizing a sedating agent, give the largest portion of the dose at bedtime. For behavioral disorders associated with dementia syndromes, use lower doses. Re-evaluate patients at a minimum of every six months. If the patient is stable, attempt to reduce the dose. Monitor the frequency and severity of psychotic symptoms and the adverse effects of medications.
Treating Psychoses with Conventional Antipsychotics

Thioridazine (Mellaril) -low potency: Initial Dose: 10-50 mg/day Range: 10-400 mg/day ADRs: sedation, anticholinergic effects, orthostatic hypotension, widening QTc interval Loxapine (Loxitane) -intermediate potency: Initial Dose: 5-20 mg/day Range: 2.5-100 mg/day ADRs: sedation, extrapyramidal symptoms, orthostatic hypotension Haloperidol (Haldol) -high potency: Initial Dose: 0.25-2 mg/day Range: 0.25-4 mg/day ADRs: extrapyramidal symptoms
Treating Psychoses with Conventional Antipsychotics

Conventional antipsychotics include low-potency agents such as thioridazine, intermediate-potency agents such as Loxitane, and high -potency agents such as haloperidol. Low potency agents tend to be more sedating and more anticholinergic, but cause fewer extrapyramidal symptoms. High potency agents are associated with a higher incidence of extrapyramidal symptoms, but produce less sedation and minimal anticholinergic effects. Comorbid conditions should be considered when selecting an agent. The selected agent should not exacerbate pre-existing conditions.
ADRs Associated with Conventional Antipsychotic Drugs: Tardive Dyskinesia

Incidence: 53% of those taking atypical antipsychotics for > 3 years (Woerner, et al, 1998) Risk Factors: Increases with dose and duration age gender (females > males) early EPS Clinical Presentation: abnormal involuntary jerking of multiple areas (e.g., tongue, extremities, trunk, diaphragm) can be irreversible Management: taper medications gradually to reduce withdrawal TD symptoms decrease risk with atypical antipsychotics no definitive treatment; prevention is key! agents used with varying success include clozapine and Vitamin E Monitoring: assess at baseline and q4-6 months test with AIMS (Abnormal Involuntary Movement Scale) or DISCUS (Dyskinesia Identification System: Condensed User Version)
ADRs Associated with Conventional Antipsychotic Drugs: Tardive Dyskinesia

Although conventional antipsychotics are effective, they are not preferred agents in the elderly due to significant adverse reactions after even relatively brief use. Tardive dyskinesia occurs in fifty-three percent of elderly patients treated with conventional antipsychotics agents after three years of cumulative exposure. Tardive dyskinesia is characterized by abnormal involuntary jerking or writhing movements that may involve multiple areas. The condition may be irreversible, and is more common in the elderly, especially older women. There is no definitive treatment for tardive dyskinesia, hence prevention is key. Interventions that have had varying success include clozapine and Vitamin E. To prevent the occurrence of withdrawal tardive dyskinesia, antipsychotic medications should be gradually tapered during discontinuation. Monitoring includes assessment at baseline and every four to six months using one of the scales listed on your screen.
ADRs Associated with Conventional Antipsychotic Drugs: Extrapyramidal Symptoms (EPS)

Pseudo Parkinsonism: Risk factors: high potency conventionals, elderly Clinical presentation: Resting tremor, cogwheel rigidity, loss of postural balance reflex, shuffling gait, dysphagia, bradyphrenia (slowed thought processes) Management: o lower dose of antipsychotic o switch to a lower potency agent o switch to an atypical antipsychotic o amantadine or benztropine may be helpful Monitoring: o baseline for 1 month, then q4-6 mos. o test with Simpson Angus Rating Scale or Extrapyramidal Symptoms Rating Scale (ESRS) Akathisia: Risk factors: high potency conventionals Clinical presentation: increased psychomotor agitation, uncontrollable urge to move, inner restlessness Management: o avoid anticholinergics o lower dose of antipsychotic o switch to a lower potency agent o switch to an atypical antipsychotic o add low doses of beta-blockers or benzodiazepines to ameliorate symptoms Monitoring: baseline for 1 month, then q4-6 months
ADRs Associated with Conventional Antipsychotic Drugs: Extrapyramidal Symptoms (EPS)

Extrapyramidal symptoms such as pseudo parkinsonism and akathisia are often associated with conventional antipsychotic therapy. These conditions can contribute to falls and loss of independent ambulation abilities in some patients. Characteristics of pseudo parkinsonism include resting tremor, cogwheel rigidity, loss of postural balance reflex, and dysphagia. Lowering the dose of the antipsychotic, switching to a lower potency agent, or switching to an atypical antipsychotic are the preferred methods of management. Amantadine or benztropine may also be added to improve symptoms.Akathisia appears as increased psychomotor agitation with the uncontrollable urge to move. In the demented elderly, it is often mistaken for worsening behavioral disturbances. Anticholinergics are not an effective treatment for akathisia. Lowering the dose of the antipsychotic or switching to a lower potency agent can be helpful. Switching to an atypical antipsychotic or adding low doses of beta-blockers or benzodiazepines may also be helpful.
Treatment of Psychosis with Atypical Antipsychotics

Advantages: improvement of negative symptoms better tolerated/fewer extrapyramidal symptoms Mechanism of Action: Serotonin (5HT2A) and dopamine (D2) antagonists Agents: clozapine (Clozaril) risperidone (Risperdal) olanzapine (Zyprexa) quetiapine (Seroquel) ziprasidone (Geodon) Mechanism of Action: Serotonin (5HT2A)antagonist and Dopamine partial agonist (D2) aripiprazole (Abilify ) Atypical antipsychotics are the preferred treatment of choice for improving negative symptoms. Clozapine is the "gold standard" for treatment of psychosis associated with Parkinsons disease; however, quetiapine is accumulating literature demonstrating benefit and may be easier to use in these patients than clozapine. Other atypical agents include risperidone, olanzapine and quetiapine. In most elderly patients, these agents are better tolerated than clozapine and they do not produce hematologic toxicity. Because of their unique mechanism of action, atypical antipsychotics cause considerably less tardive dyskinesia and extrapyramidal symptoms. Most of the available information regarding the use of atypical antipsychotics in the elderly is with risperidone, olanzapine and quetiapine. They will be discussed in detail in the following slides.
Treatment of Psychosis with Atypical Antipsychotics
There is little published information regarding the use of newer atypical agents ziprasidone or aripiprazole in the elderly. Both compounds are nearly void of anticholinergic properties which should be beneficial in disorders of cholinergic dysfunction, including Alzheimers disease. A potential problem with ziprasidone use in the elderly may be QTc prolongation which has been observed in younger adults.
Treatment of Psychosis with Clozapine (Clozaril)

Metabolism: Metabolized by CYP450 Major pathways - 1A2, 3A4 Clearance decreased by inhibitors Dosing: Initial: 6.25 mg/day Usual: 150 mg/day titrated gradually For psychosis associated with Parkinson's disease: generally < 75 mg/day Contraindications: History of myeloproliferative disorders History of granulocytopenia or agranulocytosis on clozapine Concurrent therapy with agents known to suppress bone marrow function (e.g., carbamazepine) Precautions: History of poorly controlled seizure disorder Concurrent use with benzodiazepines In geriatric patients with Parkinsons related psychosis, lower doses of clozapine are generally effective and well tolerated. For other disorders, higher doses may be needed for symptom control, but may be poorly tolerated due to severe sedation and anticholinergic effects. Clozapine is metabolized by CYP450 through the major pathways 1A2 and 3A4. Clearance of the drug is significantly decreased by inhibitors. Initial and typical doses for geriatric patients are listed on your screen. Clozapine is contraindicated in patients with a history of myeloproliferative disorders or granulocytopenia. Great caution should be exercised when giving clozapine to patients with a history of seizure disorder. Concurrent use with benzodiazepines should also be carefully monitored to reduce the risk of severe respiratory depression.
ADRs and Monitoring Guidelines for Clozapine

Adverse Drug Reactions: confusion excessive daytime somnolence orthostatic hypotension weight gain seizures (dose related) sialorrhea (excessive salivation) severe anticholinergic effects agranulocytosis (greater risk in elderly women) Monitoring Guidelines: measure orthostatic BP before each titration watch for ADRs, seizures and falls measure CBC and differential at baseline, every week for 6 months, then every 2 weeks for 6 months, every 4 weeks when stable >1 year aggressively treat constipation to avoid bowel obstruction note frequency and severity of psychotic symptoms monitor therapeutic outcomes
Clozapine is often poorly tolerated in the elderly due to severe sedation and anticholinergic effects. Other problematic adverse effects include confusion, orthostatic hypotension, and seizures. The risk of agranulocytosis requires the regular monitoring of hematologic parameters such as complete blood count and differential. Patients blood counts must be monitored closely. Seizures and falls should be assessed at that time along with therapeutic outcomes. Orthostatic blood pressure should be checked before each dose during the titration phase to prevent falls. Constipation should be monitored and aggressively treated to avoid bowel obstruction.
Treatment of Psychosis with Risperidone (Risperdal)

Metabolism: Metabolized by CYP450 Clearance decreased by 2D6 inhibitors Dosing: Initial: 0.25-0.5 mg qhs Administration: daily at bedtime or bid Maximum: up to 4 mg/day may be tolerated Maximum in dementia: 2 mg/day Adverse Drug Reactions: orthostatic hypotension, syncope, somnolence, peripheral edema, insomnia, psychomotor agitation, pseudo parkinsonism, tardive dyskinesia, increased risk of stroke Monitoring: Check orthostatic BP daily during titration Monitor for falls, parkinsonian effects Test for TD using AIMS or DISCUS at baseline and q 6 months Evaluate therapeutic outcomes by noting frequency and severity of psychotic symptoms
Treatment of Psychosis with Risperidone (Risperdal)
All the newer atypical antipsychotic agents have an improved EPS profile over conventional agents; however, risperidone can cause dose-related extrapyramidal symptoms. By restricting the maximum dose to less than two milligrams per day, these symptoms may be minimized. Adverse effects of risperidone include sedation, orthostatic hypotension, and peripheral edema. Patients on risperidone should be monitored for falls, and orthostatic blood pressure should be checked daily during the titration phase. Parkinsonian effects and tardive dyskinesia should be assessed using either the AIMS or DISCUS tests at baseline and every six months. Although the risk of tardive dyskinesia with risperidone is thought to be low, some cases have been reported. Therapeutic outcomes should be assessed by noting the frequency and severity of psychotic symptoms.
Treatment of Psychosis with Olanzapine (Zyprexa)

Metabolism: Metabolized by CYP450 1A2 Clearance decreased by inhibitors Clearance increased by inducers of 1A2 (e.g., smoking) Dosing: Initial: 2.5 mg qhs Usual: 5- 10 mg qhs Adverse Drug Reactions: orthostatic hypotension, somnolence, confusion, dizziness, weight gain, type 2 diabetes, increased lipids Monitoring: Check orthostatic BP daily during titration Monitor for falls, weight gain, parkinsonian effects Test for TD using AIMS or DISCUS at baseline and q 6 months Evaluate therapeutic outcomes by noting frequency and severity of psychotic symptoms
Treatment of Psychosis with Olanzapine (Zyprexa)
Olanzapine tends to be more sedating than risperidone, but does not appear to produce dose-related extrapyramidal symptoms within the usual geriatric therapeutic dose range. For patients especially sensitive to such symptoms, olanzapine or quetiapine may be preferred agents. The adverse effects of olanzapine include moderate somnolence, confusion, dizziness, and significant weight gain. A low incidence of extrapyramidal symptoms has been reported with this agent. Patients on olanzapine should be monitored for falls, weight gain, and pseudo parkinsonism. Orthostatic blood pressure should be checked daily during titration, as sedation tends to be the most severe during initial titration. Patients should be assessed for tardive dyskinesia with theAIMS or DISCUS instruments at baseline and every six months.
Treatment of Psychosis with Quetiapine (Seroquel)

Metabolism: Metabolized by CYP450 3A4 Clearance decreased by inhibitors Clearance increased by inducers Dosing: Initial: 25 mg daily - bid Typical: 75-150 mg/day divided bid (AM & HS) Adverse Drug Reactions: severe somnolence during titration, orthostatic hypotension, confusion, dizziness Monitoring: Check orthostatic BP daily during titration Monitor for falls, sedation, parkinsonian effects, TD Check for signs of hypothyroidism Evaluate therapeutic outcomes by noting frequency and severity of psychotic symptoms
Another atypical antipsychotic, quetiapine, is metabolized by cytochrome P450 3A4.Initial and typical dosing guidelines are listed on your screen. Quetiapines adverse effects include moderate to severe somnolence during the initial titration period, confusion, dizziness, and orthostatic hypotension. Quetiapine can produce significant initial sedation, but has a very low potential for extrapyramidal symptoms. It may be an alternative to clozapine in psychoses associated with Parkinson's disease. Patients taking quetiapine should be monitored for adverse effects commonly associated with the newer atypical agents. The incidence of hypothyroidism associated with this drug may be increased in elderly women.
Metabolic, Cardiovascular and Cerebrovascular Effects Associated with Atypical Antipsychotics

Metabolic Increased risk of developing Type 2 Diabetes Mellitus and lipid disorders, but exact mechanism is unknown Hyperglycemia and Diabetes Mellitus Added to Warnings section - Effects all atypical antipsychotics The weight gain seen with these agents does not appear to be a risk factor, but may exacerbate the condition Cardiovascular Clozapine is associated with a number of potential adverse effects on the cardiovascular system All other atypicals derive their potential cardiovascular effects on their effects on a1, M1 receptors and iKr channels Clozapine, risperidone most likely to cause orthostasis Clozapine most likely to cause sinus tachycardia from anticholinergic effects Ziprasidone has greatest effects on QTc duration Cerebrovascular Cerebrovascular events have been reported in trials of risperidone and olanzapine in elderly patients with dementiarelated psychosis Cerebrovascular events language added to Warnings section for risperidone, olanzapine Cerebrovascular events language added to Precautions section for aripiprazole, ziprasidone, quetiapine The atypical antipsychotics should be used with caution in patients at risk for diabetes and cerebrovascular events Patients taking atypicals should be monitored for signs of lipid abnormalities, signs of glucose intolerance and cerebrovascular events
Metabolic, Cardiovascular and Cerebrovascular Effects Associated with Atypical Antipsychotics

The risk of developing hyperglycemia, Type 2 Diabetes Mellitus and lipid disorders has been reported in patients prescribed atypical antipsychotics. A direct causal link between the development of metabolic adverse effects and atypical antipsychotics has not been established but it appears greater with agents such as clozapine and olanzapine. While this effect may be independent of the weight gain often seen with these agents, weight gain may also exacerbate these conditions, creating a viscous cycle. A higher incidence of cerebrovascular adverse events such as stroke and transient ischemic attacks, which may be fatal, have been reported in patients treated with risperidone or olanzapine in placebo controlled trials of elderly patients with dementia-related psychosis. Atypical antipsychotics should be used with caution in patients at risk for developing diabetes and cerebrovascular events and such patients should be monitored for signs of glucose intolerance and lipid abnormalities.
Antipsychotic Drug Interactions

Pharmacokinetic Interactions: all antipsychotics extensively metabolized through CYP450 system, leading to many possible interactions antipsychotic + enzyme inhibitor: increased serum antipsychotic levels and possible ADRs antipsychotic + enzyme inducer: decreased serum antipsychotic levels and possible therapeutic failure Pharmacodynamic Interactions: Sedation: with benzodiazepines, anticonvulsants; increased risk of falls, and confusion Anticholinergic effects: with antihistamines, oxybutynin; increased risk of urinary retention, constipation, and delirium Orthostatic hypotension: with antihypertensives, diuretics, vasodilators; increased risk of falls
All antipsychotic medications undergo extensive hepatic metabolism mediated by the cytochrome P450 system. Concurrent use of an antipsychotic with an inhibitor may lead to increased adverse effects such as extrapyramidal symptoms. In combination with an enzyme inducer, lower than anticipated serum levels may occur with consequent therapeutic failure. Pharmacodynamic drug interactions are also common in the elderly. The additive sedative effects of an antipsychotic and a benzodiazepine, for example, can lead to confusion and falls while additive anticholinergic effects may contribute to the development of a drug-induced delirium.
Neuroleptic Malignant Syndrome (NMS)

Incidence: rare, but potentially fatal Onset: sudden Clinical Presentation: fever muscle rigidity altered mental status widely fluctuating BP and pulse cardiac dysrhythmias substantial increase in CPK Management: discontinue antipsychotic immediately seek supportive treatment as needed
Neuroleptic malignant syndrome or NMS is a rare but potentially fatal complication of antipsychotic drug therapy. If suspected, medical attention should be sought and the antipsychotic drug should be discontinued. Because some of the symptoms of neuroleptic malignant syndrome may mimic flu-like illness in the elderly, NMS may be difficult to diagnose. Any geriatric patient receiving an antipsychotic drug that suddenly develops a fever and rigidity should be promptly assessed for this condition.
Resources
For additional information, see: Bullock R, Saharan A (2002). Atypical antipsychotics: Experience and use in the elderly. Int J Clin Pract 56:515-525. Caligiuri MR, Jeste DV, Lacro JP (2000). Antipsychotic-Induced movement disorders in the elderly: epidemiology and treatment recommendations. Drugs Aging. 17: 363-84. Dolder CR and Jeste DV (2003). Incidence of tardive dyskinesia with typical versus atypical antipsychotics in very high risk patients. Biol Psychiatry 53:1142-1145. Ereshefsky, L. (1996). Pharmacokinetics and drug interactions: update for new antipsychotics. J Clin Psychiatry:57[suppl 11]:12-25. Jeste, D. V., Eastham, J. H., Lacro, J. P., Gierz, M., Field, M. G. & Harris, M. J. (1996). Management of late-life psychosis. Clin Psychiatry; 57 (suppl 3):39-45. Katz IR, Jeste DV, Mintzer JE et al (1999). Comparison of risperidone and placebo for psychosis and behavioral disturbances associated with dementia: A randomized, double-blind trial. J Clin Psychiatry 60:107-115. Kindermann SS, Dolder CR, Bailey A, et al (2002). Pharmacological treatment of psychosis and agitation in elderly patients with dementia: four decades of experience. Drugs Aging 19: 257-76. Kumar, V. (1997). Use of atypical antipsychotic agents in geriatric patients: a review. International Journal of Geriatric Psychopharmacology; 1:15-24.
Resources
Howard R, Rabins PV, Seeman MV, Jeste DV (2000).Late-onset schizophrenia and very-late-onset schizophrenia-like psychosis: an international consensus. The International Late-Onset Schizophrenia Group. Am J Psychiatry. 157: 172-8. Sernyak MJ, Leslie DL, Alarcon RD, et al (2002). Association of diabetes mellitus with use of atypical neuroleptics in the treatment of schizophrenia. Am J Psychiatry 159:561-56. Snowden M, Sato K and Roy-Byrne P (2003). Assessment and treatment of nursing home residents with depression or behavioral symptoms associated with dementia: a review of the literature. J Am Geriatr Soc 51:1305-1317. Sweet JS, Clark WS, Gannon KS et al (2000). Olanzapine treatment of psychotic and behavioral symptoms in patients with alzheimer disease in nursing care facilities: A double-blind, randomized, placebo-controlled trial. Arch Gen Psychiatry 57:968-976. Tariot PN, Salzman C, Yeung PP, et al (2000). Long-term use of quetipine in older patients with psychotic disorders. Clin Ther 22:1068-1084. Tune LE, Salzman C (2003). Schizophrenia in late life. Psychiatr Clin North Am. 26: 103-13 Woerner, M. G., Alvir, J. M., Saltz, B. L., et al. (1998). Prospective study of tardive dyskinesia in the elderly: rates and risk factors. Am J Psychiatry; 155:1521-1528.
Resources
Woo BKP, Daly JW, Allen ED, et al (2003). Unrecognized medical disorders in older psychiatric inpatients in a senior behavioral health unit in a university hospital. J Geriatr Psychiatry Neurol 16:121-125. Zayas, E. M. & Grossberg, G. T. (1998). The treatment of psychosis in late life. J Clin Psychiatry;59[suppl 1]:5-10. Organizations The National Alliance for the Mentally Ill (NAMI) Colonial Place Three National Mental Health Association (NMHA) National Mental Health Consumers' Self-Help Clearinghouse
Depression
Learning Objectives: By the end of this review concept, you will be able to: Describe the epidemiology of depression in the elderly. List the common etiologies of major depression and agents that can cause drug-induced depression. List the signs and symptoms of major depression. Differentiate the clinical presentation of dementia with that of depression. Describe procedures and criteria for diagnosing depression in the elderly. Describe pharmacological and nonpharmacological options for the treatment of depression. Describe mechanism of action, clinical benefits, dosing, adverse effects and monitoring protocols for agents used in the treatment of depression in the elderly. Describe pharmacokinetic and pharmacodynamic interactions associated with the use of antipsychotic therapy. Summarize guidelines for the selection, implementation, and discontinuation of antidepressant therapy.
Depression in the Elderly

Clinical Characteristics: treatable and often recurrent impairs social, cognitive and physical functioning commonly misdiagnosed and untreated may present with somatic complaints Epidemiology of Late-Life Depression: Rate of major depressive disorder among community dwelling elderly population is 1-2% In long-term care facilities, 30-40% experience depressive symptoms and 12-16% meet diagnostic criteria for major depressive disorder elderly women> elderly men 31% of Long Term Care Facility (LTCF) residents report new episodes and symptoms Mortality: LTCF residents have 60% higher risk of death during first year causes of mortality: suicide (men > women) worsening of comorbid conditions
Depression in the Elderly
Depression is a treatable, cyclic disorder that can impair a persons ability to function socially, cognitively and physically. Unfortunately, in the elderly, depression is commonly untreated and misdiagnosed because it is commonly mistaken for other comorbid disorders, such as dementia. Many professionals and family members may consider symptoms of depression as a normal result of aging, and do not recognize the condition. Community-based studies have found 1 to 2 percent of the elderly meet the strict criteria for major depressive disorder. However, as many as 15 to 25 percent may experience depressive symptoms. These rates rise dramatically in the long term care setting where as many as 30 to 40 percent experience depressive symptoms and as many as 12 to 16 percent fulfill diagnostic criteria for major depression. Major depression is more common in elderly women than in elderly men. Among the thirty-one percent of long term care residents who report new episodes and symptoms, the presence of depression can increase the risk of death by almost sixty percent within the first year in the facility. Depressed elderly, particularly elderly males have higher rates of suicide than the general population. If left untreated, depression can also worsen comorbid conditions, contributing ultimately to death.
Etiologies of Major Depression

Psychological: loss negative self-evaluation Psychosocial: isolation lack of social support Medical: hypothyroidism anxiety Alzheimers disease Parkinsons disease post CVA hypertension arthritis alcoholism metabolic disorders cardiovascular disease Pharmacological
Major depression can be caused by psychological, psychosocial, medical and pharmacological factors. Psychological factors that can bring on major depression include experiencing the loss of a partner, home or daily functioning. Psychosocial factors can also trigger major depression in the elderly, especially in those individuals that lack adequate support systems. Two of the most common causes of depression in the elderly are comorbid medical conditions and pharmacological agents. Diseases that can lead to depression are listed on your screen. Depression can be a presenting symptom of many disorders, as it is in more than half the cases of Parkinsons disease.
Drug-Induced Depression
H2 Antagonists Cimetidine Ranitidine Anti-inflammatory Agents/Analgesics Opioids Phenylbutazone Indomethacin Cardiovascular Agents Guanethidine Methyldopa Reserpine Hydralazine Propranolol Prazosin Clonidine Digitalis Calcium channel blockers Thiazide Diuretics
Steroids Corticosteroids Anabolic Steroids Estrogen ?? Antiparkinsonian Agents Levodopa Sedative-hypnotic agents Alcohol Barbiturates Chloral hydrate Benzodiazepines Meprobamate Others Amphetamine Withdrawal Baclofen Metoclopramide Conventional antipsychotics
Symptoms of depression may also appear as an adverse effect of pharmacotherapy for many medical conditions. A list of the drugs that have been linked to depressive symptoms is displayed. It is important to realize that not everyone receiving one of these medications will develop major depression. The cause of depression in a person receiving treatment is not always causally related to a particular medication. This list indicates some medications that have been associated with the development of depressive symptoms and should be considered when evaluating the possible causes of depression.
DSM-IV-TR Signs and Symptoms of Major Depression

At least 5 or more symptoms for at least 2 weeks: insomnia or hypersomnia changes in weight & appetite psychomotor agitation or retardation fatigue or anergia irritable mood feelings of worthlessness or inappropriate guilt concentration impairment anhedonia (decreased interest in pleasurable activities) suicidal thoughts or actions
Depression can significantly impair an individuals level of functioning. In addition to a decrease in physical and cognitive performance, the person is often unable to manage basic activities of daily living. Specific symptoms include those listed here as noted in the Diagnostic and Statistical Manual. At least five or more of these symptoms must be present all or most of the day for at least two weeks to be considered diagnostic of major depressive disorder.
Depression versus Dementia

Dementia Cognition impaired Remote memory consistent Apathy Disorientation Variable affect Depression Cognition intact Concentration inconsistent Depressed mood Orientation intact Depressed or anxious affect
Depressed patients often experience problems with memory of recent events and difficulties with tasks requiring concentration. In the elderly, these symptoms are also characteristic of dementia. "Pseudodementia" describes depressionrelated memory impairment. In patients with no underlying cognitive impairment, pseudodementia is fully reversible with effective treatment of the depressive illness.
Diagnostic Evaluation of Major Depression
Clinical Interview: medical history history of depressive episode substance abuse drug regimen Physical Examination: blood pressure mental status neurological evaluation
Lab Tests: CBC with differential folate, B12 serum electrolytes urinalysis chest x-ray ECG TSH Psychological Tests: Geriatric Depression Scale Hamilton Rating Scale for Depression Cornell Scale for Depression in Dementia Mini-Mental State Examination (MMSE)
In diagnosing depression, substance use or abuse, and underlying medical problems should be ruled out first. The clinical interview is fundamental to determining not only functional status and medical history, but also length of the depressive episode, history of previous episodes, family history of depression, and history of drug and alcohol abuse. Response to previous treatment for depression, suicidal ideation or attempts, and level of physical functioning should be also documented at this time. A review of the current drug regimen is essential. The physical exam should include a mini-mental state examination to assess impairment of cognitive functioning. Lab tests should include complete blood count with differential, urinalysis, and chest x-ray. Psychological screening tests such as the Geriatric Depression Scale, Hamilton Rating scale for Depression, or Cornell Scale for Depression in Dementia are also necessary for accurate assessment.
Treatment for Depression

Cognitive-behavioral Psychotherapy: changes the behavior and thoughts helps patient gain new perspectives Antidepressant Pharmacotherapy: promotes remission of symptoms prevents recurrences contributes to drug-drug interactions and significant adverse effects requires close monitoring Electroconvulsive Therapy (ECT): indicated for patients who do not respond to other therapies safe and effective unilateral treatments decrease occurrence of severe irreversible memory impairment
Treatment for Depression
Depression can be treated with a variety of therapies including pharmacotherapy, psychotherapy, and electroconvulsive therapy. Cognitive-behavioral psychotherapy includes changing the behavior and thoughts of the depressed person. The objective of therapy is to generate new interpretations for ones life. Psychotherapy is most effective when used with pharmacotherapy, which is generally the cornerstone of treatment for the majority of depressed elderly. Antidepressants can promote the remission of symptoms and prevent recurrences. However, antidepressants may also contribute to pharmacokinetic or pharmacodynamic interactions that lead to significant adverse effects. For those severely depressed who do not respond to antidepressant drug therapy, electroconvulsive therapy is considered to be a safe and effective means of treating severe geriatric depression. Refinement of the procedure, with unilateral treatments, has been found to decrease the occurrence of severe irreversible memory impairment.
Treatment of Depression with Antidepressants

Selective serotonin reuptake inhibitors (SSRIs) Serotonin reuptake inhibitor and serotonin-2(5-HT2) antagonists Dopamine (DE) and norepinephrine (NE) reuptake inhibitors Norepinephrine, serotonin and dopamine reuptake inhibitors Alpha-2 antagonists, serotonin-2 antagonists (5-HT2), and serotonin-3 (5-HT3) antagonists Mixed norepinephrine (NE) and serotonin (5-HT) reuptake inhibitors (TCAs) Monoamine oxidase inhibitors (MAOIs)
Antidepressants yield about a sixty percent remission rate in the depressed elderly, as compared to thirteen percent with placebo treatment. They can be categorized by their effects on various neurotransmitters and receptors, as shown here. The tricyclic antidepressants and monoamine oxidase inhibitors are effective antidepressants, but due to significant side effects at therapeutic dosages and narrow therapeutic index, they are considered to be second line therapy for geriatric patients. Conservative dosing and slow titration of antidepressants is recommended. Generally, patients should be treated for at least six months after their initial response to antidepressant therapy.
Treatment of Depression with Selective Serotonin Reuptake Inhibitors (SSRIs)

Mechanism of Action: block the reuptake of serotonin Advantages: no significant cardiovascular effects minimal sedative and anticholinergic effects (except for paroxetine) Agents: fluoxetine (Prozac) Initial dose: 10 mg/d Usual adult range: 10-50 mg/d ADRs: nervousness, insomnia sertraline (Zoloft) Initial dose: 12.5-25 mg/d Usual adult range: 25-150 mg/d ADRs: sexual dysfunction, insomnia paroxetine (Paxil) Initial dose: 10 mg/d Usual adult range: 10-40 mg/d ADRs: dry mouth, sedation fluvoxamine (Luvox) Initial dose: 25 mg/d Usual adult range: 25-150 mg/d ADRs: severe GI distress (esp. during titration), dizziness, somnolence citalopram (Celexa) Initial dose: 10-20mg/d Usual adult range: 20-40mg/d ADRs: nausea, vomiting, diaphoresis escitalopram (Lexapro) Initial dose: 10 mg/d Usual adult range: 10-20mg/d ADRs: nausea, vomiting, diaphoresis All SSRIs are metabolized by and inhibit CYP450 enzymes, but citalopram and sertraline are the least likely to be involved in drug interactions Do not combine with MAOIs
Treatment of Depression with Selective Serotonin Reuptake Inhibitors (SSRIs)
Safer and better tolerated than earlier agents, the selective serotonin reuptake inhibitors are considered first line therapy for many elderly patients. S-S-R-Is act by blocking the reuptake of serotonin, and cause fewer cardiovascular, anticholinergic and sedative effects than tricyclic antidepressants. Commonly used agents include fluoxetine, sertraline, paroxetine, fluvoxamine and citalopram. Geriatric dosage requirements and adverse effects are listed for each drug. Doses must be individualized to optimize response and minimize adverse effects. Due to decreases in clearance related to age and organ function, actual geriatric maintenance dosages may be less than the usual adult maximum dosage. Adverse effects of selective serotonin reuptake inhibitors include headache, nausea, and diarrhea. These agents may also exacerbate insomnia, but are less likely to cause severe cognitive impairment. The potential for extrapyramidal adverse effects, druginduced SIADH, and drug-drug interactions should be considered.
Treatment of Depression with Serotonin Reuptake Inhibitors and 5-HT2 Antagonists

Trazodone (Desyrel): rarely used as an antidepressant due to ADR profile in low doses, utilized as a hypnotic or augmenting agent weak anticholinergic effects Dosing: Typical dose: 25-100mg qhs Daytime divided dosing for anxiolytic effects ADRs: sedation, confusion, orthostatic hypotension, ventricular arrhythmias, priapism Nefazodone (Serzone) more tolerable than trazodone excellent early onset anxiolytic activity low anticholinergic and cardiovascular effects Dosing: Initial: 50-100 mg/day divided doses bid Usual adult range: 100-400 mg/d ADRs: somnolence, dry mouth, and nausea, orthostasis less than trazodone.Liver failure (rare). Do not combine with MAOIs
Treatment of Depression with Serotonin Reuptake Inhibitors and 5-HT2 Antagonists
Serotonin reuptake inhibitors and 5-H-T-2 antagonists include trazodone and nefazodone. Trazodone is rarely used to treat elderly depression. It is primarily used as a hypnotic, often added to S-S-R-I therapy in patients with severe sleep disturbances. The usual geriatric dose range is twenty-five to one hundred milligrams per day, and the most common adverse effects include sedation, confusion and orthostatic hypotension. Ventricular arrhythmias have resulted from use in some patients with preexisting cardiac disease. Nefazodone has a better tolerability profile. It selectively inhibits presynaptic reuptake of serotonin, and antagonizes postsynaptic 5-H-T-2 receptors. Nefazodone can be successfully utilized in the treatment of depression with severe anxiety symptoms. It modestly reduces resting pulse and supine blood pressure, and has low anticholinergic and cardiovascular effects. Adverse effects include somnolence, dry mouth, and nausea. It has also received a black box warning of life threatening hepatic failure.
Treatment of Depression with Tricyclic Antidepressants (TCAs)

Tertiary Amines: amitriptyline, imipramine, and doxepin have increased anticholinergic SE and sedation should not be used in elderly. Secondary Amines: desipramine and nortriptyline have less anticholinergic SE AMDA practice guidelines recommend their use in younger, healthier nursing home patients. Desipramine (Norpramin) and Nortriptyline (Pamelor) nortriptyline least likely to cause orthostasis Dosing: Desipramine: 25-100mg qd Nortriptyline: 30-50 mg in divided doses or qd start with low dose and increase gradually Adverse Drug Reactions: less sedation than tertiary, orthostasis, minimal anticholinergic SE (dry mouth, constipation, etc.) photosensitivity, bluegreen urine with desipramine Precautions: Due to risk of overdose, drugs should not be given to suicidal patients
Treatment of Depression with Tricyclic Antidepressants (TCAs)
Tricyclic antidepressants include both tertiary and secondary amines.The secondary amines, desipramine and nortriptyline, are the active metabolites of the tertiary amines imipramine, and amitriptyline, respectively. This is why they both have less anticholinergic side effects when compared to the tertiary amines. Since elderly patients are susceptible to anticholinergic side effects, it is recommended that only the secondary amines be used. Because these drugs can be very dangerous if the patient overdoses, they should never be given to suicidal patients. Desipramine and nortriptyline should be started at low doses and slowly titrated up.The usual dose for desipramine is 25-100mg per day and the usual dose for notriptyline is 30-50mg per day. Adverse effects include minimal anticholinergic side effects, photosensitivity, and orthostasis. Nortriptyline is the least likely to cause orthostasis. Also, desipramine may impart a blue-green color to urine.
Treatment of Depression with Dopamine and Norepinephrine Reuptake Inhibitors

Bupropion (Wellbutrin SR) a dopamine and norepinephrine reuptake inhibitor exerts effects through both dopaminergic and norepinephrine system no orthostatic hypotension or cardiotoxicity minimal anticholinergic effects with SR formulations, risk of seizures are significantly decreased when compared to IR formulations Dosing: Initial: 100 mg SR qd Usual adult range: 150-300 mg/day bid ADRs: insomnia and CNS stimulation metabolized by, but does not inhibit CYP450 system
Venlafaxine (Effexor) a norepinephrine, serotonin, and dopamine reuptake inhibitor short half-life: IR formulation is given bid, SR formulation allows qd dosing Dosing: Initial: 12.5-25 mg qd Usual adult range: 50-225 mg/day bid SR dosages include Effexor XR 37.5 mg, 75 mg, 150mg Active metabolite is renally eliminated; decrease dose 50% for CLCr < 30 mL/min

ADRs: nausea, vomiting, headache dose-related BP elevation: incidence of significant increases (diastolic > 90 mmHg) is 3% at doses < 100 mg/day, up to 13% at doses > 300 mg/day few drug-drug interactions metabolized by, but does not inhibit CYP450 system Duloxetine (Cymbalta) a norepinephrine and serotonin reuptake inhibitor exerts more potent norepinephrine activity at lower doses versus venlafaxine Also indicated for diabetic neuropathy Dosing Initial: 20 mg twice a day Usual adult range: 60 mg/day (can be given once daily or twice daily Diabetic neuropathy dose: 60 mg everyday ADRS: insomnia, headache, nausea, elevation in blood pressure Do not use medication in patients with hepatic insufficiency, or in patients with CrCl less than 30 ml/min Monitoring: LFT's should be done periodically
Do not combine with MAOIs
Dopamine and norepinephrine reuptake inhibitors include bupropion and venlafaxine. Bupropion does not cause orthostatic hypotension or arrhythmias, and has minimal anticholinergic effects. Furthermore, the risk of seizures with sustained release bupropion is less than the IR formulation and thought to be no greater than the risk seen with the selective serotonin reuptake inhibitors. Bupropion can cause insomnia and central nervous system stimulation; hence the last dose should be given no later than five pm. The immediate release formulation must be administered three times day in doses no greater than one hundred fifty milligrams. Like bupropion, venlafaxine comes in immediate release and sustained release formulations. Because of its short half-life, immediate release venlafaxine requires multiple daily dosing. The sustained release formulations are dosed once daily. This agent has side effects similar to SSRI's, and the potential for adverse cardiovascular effects such as dose-related increase in diastolic blood pressure. The most common adverse effect is doserelated nausea, which may be minimized if given with food. Like venlafaxine, duloxetine is a norepinephrine and serotonin reuptake inhibitor. Duloxetine can be given twice a day or once daily based on indication for utilization. Besides treating major depression, duloxetine also has the approval to treat diabetic neuropathy. Most adverse events are similar to that of venlafaxine, however, monitoring of the LFT must be done periodically. Duloxetine should be avoided in patients with known renal and hepatic insufficiency.
Treatment of Depression with Alpha-2 Antagonist, Serotonin-2 Antagonist (5-HT2), and Serotonin-3 (5-HT3) Antagonist
Mirtazapine (Remeron) early improvement in depression-associated anxiety long half-life of 20-40 h allows qd dosing metabolized by, but does not inhibit CYP450 system Dosing: Initial: 7.5-15mg qhs Usual adult range: 15-45 mg/day ADRs: sedation, dizziness, significant weight gain (due to histamine blockade), agranulocytosis(rare) Do not combine with MAOIs
Mirtazapines blockade of 5-HT3 receptors mitigates the nausea often observed with drugs that inhibit serotonin reuptake such as selective serotonin uptake inhibitors and venlafaxine. Mirtazapine exhibits early onset of anxolytic and hypnotic effects; patients with anxiety or severe sleep disturbance may benefit. Due to mirtazapine's long half-life, dosage increases should be made at no less than one week intervals. Mirtazapines blockade of histamine is responsible for adverse effects such as sedation and weight gain.
Treatment of Depression with Monoamine Oxidase Inhibitors (MAO-I)

Oral Isocarboxazid (Marplan) Phenelzine (Nardil) Tranylcypromine (Parnate) Rarely used in the geriatric patient Must limit tyramine in diet and avoid sympathomimetics ADR's: Hypertensive crisis, orthostatic hypotension, weight gain, headache Must be antidepressant free for two weeks prior to initiation of MAO-I, with exception of fluoxetine, which must be at least 5 weeks off prior to starting MAO-I Transdermal Selegiline (EMSAM) Useful if patient is NPO or has difficulty swallowing Available in 6mg/day, 9 mg/day, and 12mg/day Patch must be changed daily No changes in dietary modification (tyramine intake) required at 6mg/day Most common adverse event is local skin reaction Although the MAO-I's are rarely seen to treat major depression, they are still a viable option to treat a severely depressed patient, especially if the patient is treated in a LTC facility where food intake is closely monitored. Tyramine intake should be eliminated in patients treated with an MAO-I to ensure that the patient does not develop a hypertensive crisis. Another option to treat a severely depressed patient is with the selegiline patch indicated for the treatment of major depression. Once nice characteristic of the selegiline patch is that the patient does not need any dietary changes, or reduction in tyramine containing foods, at the 6mg/day patch. The patch does need to be removed and exchanged everyday. The most common adverse event reported with the patch is a local site reaction.
Antidepressant Tapering and Discontinuation

Consequences of Discontinuation: TCAs: nausea, anxiety, sleep disturbance, flu-like symptoms SSRIs: anxiety, irritability, flu-like symptoms, dizziness, and paresthesias To avoid Discontinuation Symptoms: Taper gradually Evaluate symptoms of depression regularly Assess long term use toxicity Tapering Guidelines: paroxetine 10 mg every 5-7 days sertraline 50 mg every 5-7 days fluvoxamine 50 mg every 5-7 days venlafaxine 25 mg every 5-7 days fluoxetine- no tapering necessary
Discontinuation of antidepressant therapy abruptly can cause discontinuation syndrome. If tricyclic antidepressants are discontinued abruptly, symptoms of "cholinergic rebound" such as nausea, anxiety, sleep disturbance and flu-like symptoms often occur. When selective serotonin reuptake inhibitors are discontinued abruptly, anxiety, dizziness, and paresthesias may result. Generally, antidepressants should be slowly discontinued, tapering off over two to four weeks Following discontinuation of antidepressant therapy, patients should be monitored closely for recurrence of depressive symptoms.
Antidepressant Pharmacokinetic and Pharmacodynamic Interactions

Pharmacokinetic Interactions: many newer antidepressants inhibit CYP450 system significant interactions: 1A2, 2C19, 2D6, 3A4 hepatic enzyme inhibition characteristic of most SSRIs patients with multiple medications at highest risk Pharmacodynamic Interactions: most dangerous ADR = serotonin syndrome caused by serotonergic antidepressants occurs with MAOIs + SSRIs or with combinations of serotonergic agents(e.g., SSRI + dextromethorphan) symptoms include tremor, myoclonus, seizures, agitation, fever, shivering, diarrhea and abdominal pain
Interactions of antidepressants occur by pharmacokinetic or pharmacodynamic mechanisms. Pharmacokinetic interactions involve the induction or inhibition of hepatic drug metabolizing enzymes, specifically cytochrome P-450 enzymes. Significant drug-drug interactions may involve 1A2, 2C19, 2D6, and 3A4 isoenzymes. Hepatic enzyme inhibition is largely an effect of selective serotonin reuptake inhibitors, however, potency of inhibition varies among agents. Of the S-S-R-Is, sertraline and citalopram are less likely to be implicated in significant interactions. In addition, bupropion, venlafaxine, and mirtazapine do not significantly inhibit major metabolic pathways. In many cases, concurrent use of an inhibitor and a substrate is not contraindicated; however, patients should be observed for toxicity or other negative outcomes of combination therapy. The most dangerous adverse reaction involving the serotonergic antidepressants is the serotonin syndrome. Caused by serotonergic hyperstimulation, symptoms may include tremor, myoclonus, seizures, agitation, fever, shivering, diarrhea and abdominal pain. If suspected, all serotonergic agents must be discontinued immediately and supportive measures employed, if necessary.
Monitoring and Maintaining Antidepressant Therapy

Monitor: adequate dosage duration of therapy Maintain for life in patients: age > 40 years + 2 episodes age > 50 years + 1 episode any age + 3 episodes Recurrence Rates: 50% recurrent symptoms within 2 years 80-90% recurrent depression after 2nd episode
Close monitoring of antidepressants through serial clinical interviews and depression inventories is essential in elderly patients. An adequate dosage must be provided for a specific duration to assess the effectiveness of any given agent. Drug therapy should continue for six months after remission of symptoms. Adverse effects occurring during long-term administration should be monitored and addressed. Lifetime therapy is generally recommended for those with the onset of depression after age fifty. Depression tends to be cyclical. Fifty percent of patients experience recurrent symptoms within the first two years, and eighty to ninety percent experience recurrent depression after a second episode.
Factors That Determine Choice of Therapy

severity of episode and symptoms co-morbid medical conditions interactions drug review regimen costs previous response to antidepressant agents adverse effect profile of agents dosing regimen complexity age
Several factors will influence the type of therapy used to treat depression. Such factors include the severity of the depressive episode and symptoms. Since comorbid medical conditions can increase susceptibility to adverse effects of certain drugs, they should be considered as well. Drugs that cause orthostatic hypotension are dangerous in the elderly due to risk of fractures and falls and should not be utilized in this population. Cost is a factor that influences selected therapy, but previous response to an antidepressant agent, the adverse effect profile of the agent, and dosing regimen complexity should also be considered.
Resources
For additional information, see: Alexopoulos GS, Bruce ML, Hull J, et al (1999). Clinical determinants of suicidal ideation and behavior in geriatric depression. Arch Gen Psychiatry 56:1048-1053. Blazer D, Hughes DC, George LK (1987). The epidemiology of depression in an elderly community population. Gerontologist 27:281-287. Beers, MH & Berkow, R. (2000). Depression The Merck Manual of Geriatrics. 3nd edition Section 4, Psychiatric Disorders. Whitehouse Station, NJ: Merck Research Laboratories: 310-321. Feinberg, M., Dinwiddie, J. & Wells, B. G.(1997). Depression in the elderly. American Society of Consultant Pharmacists. Finkel, S. I. (1996).Efficacy and tolerability of antidepressants therapy in the old-old. J Clin Psychiatry; 57 (suppl 5): 23-8. Lebowitz BD, Pearson JL, Schneider LS et al (1997). Diagnosis and treatment of depression in late life. Consensus statement update. JAMA 278:1186-1190. Mittmann N, Herrmann N, Einarson TR et al (1997). The efficacy, safety and tolerability of antidepressants in late life depression. J Affect Disord 46:191-217. Montgomery SA (2002). Late-life depression: Rationalizing pharmacological treatment options. Gerontology 48:392-400. Montgomery SA, Beckman ATF, Sadavoy J, et al (2000). Consensus statement on depression in the elderly. J Clin Psychiatry 2000;2:46-52.
Resources
NIH Consensus Development Panel on Depression in late life. (1992). Diagnosis and treatment of depression in later life. JAMA; 268: 1018-24. Snowden M, Sato K and Roy-Byrne P (2003). Assessment and treatment of nursing home residents with depression or behavioral symptoms associated with dementia: A review of the literature. J Am Geriatr Soc 51:1305-1317. Streim JE, Oslin DW, Katz IR, et al (2000). Drug treatment of depression in frail elderly nursing home residents. Am J Geriatr Psychiatry 8:150-159. Zisook, S. & Downs, N. S. (1998). Diagnosis and treatment of depression in late life. J Clin Psychiatry; 59(suppl 4):80-91.
Bipolar
By the end of this review concept, you will be able to: Describe the clinical characteristics and epidemiology of bipolar disorder. List the signs and symptoms of bipolar disorder, including both manic and depressive phases. Describe agents and approaches commonly used in the acute and prophylactic treatment of bipolar disorder in the elderly. Compare and contrast dosing, adverse reactions, drug-drug interactions and monitoring guidelines for agents commonly used to treat bipolar disorders in the elderly.
Clinical Characteristics and Epidemiology of Bipolar Disorder

Clinical Picture: Cyclic manic and depressive episodes Condition may be genetically linked, but less so if onset occurs late in life Often acquired in youth Older patients episodes may be longer and more frequent Clinical presentation varies widely Incidence and Mortality: Less prevalent than depression in elderly (5-10% of mood disorders) Occurs in men and women with equal frequency Affects 1.0 to 3.7% of general population 10-15% of those affected commit suicide Patients with bipolar disorder may experience dramatic mood swingsfrom feelings of being overly high and/or irritable to sad and hopeless, and then back again, often with periods of normal mood in between. Severe changes in energy and behavior coincide with these changes in mood. The periods of highs and lows are called episodes of mania and depression. The episodes tend to repeat, with an average of four in a ten-year period. Some patients experience decreasing intervals between cycles with age. Bipolar disorder typically develops in late adolescence or early adulthood. However, some people have their first symptoms during childhood, and some develop them late in life. In patients over 65 years of age, prevalence rates of bipolar disorder range from 0.1% to 0.4%. The disorder has been found to be genetically linked, and occurs equally among men and women. Onset of mania after age 60 is less likely to be associated with a family history of bipolar disorder and is more likely to be associated with identifiable general medical factors, including stroke or other central nervous system lesion. They may also have longer episode durations or more frequent episodes of illness.
Of those affected, ten to fifteen percent commit suicide. For this reason, aggressive treatment and prophylactic therapy is required throughout the bipolar patient's lifetime.
Signs and Symptoms of Bipolar Disorder

Manic Cycle: Elated, expansive, or irritable mood Symptoms are present for at least 1 week, and 3 or more of the following symptoms: Inflated self-esteem Decreased need for sleep More talkative than usual Flight of ideas (racing thoughts) Distractibility Increased goal-directed psychomotor activity Involvement in activities with painful consequences Depressive Cycle: Depressed or irritable mood Insomnia or hypersomnia Fatigue or anergia Feelings of worthlessness or inappropriate guilt Concentration impairment Anhedonia (decreased interest in pleasurable activities) Bipolar disorder is characterized by one or more manic episodes alternating with depression. Manic episodes are characterized by a euphoric or irritable mood accompanied by decreased sleep, hyperverbalization, and often grandiose delusions. A change in sleep patterns is often a first sign of the onset of a manic phase. Patients often appear to have difficulty concentrating or focusing on even simple tasks. Depressive episodes are characterized by the familiar signs and symptoms of conventional depression. Depression is more common in women with bipolar disorder.
Pharmacological Treatment and Prophylaxis of Bipolar Disorder

Agents: Lithium carbonate (Lithobid) Valproate (Depakene) Carbamazepine (Tegretol, Equetro) Lamotrigine (Lamictal) Atypical antipsychotics (Risperdal, Zyprexa , Seroquel, Geodon, Abilify) Combination product, olanzapine and fluoxetine (Symbyax) Antidepressants Approaches: Monotherapy first Combination therapy Cautious use of antidepressants Lifetime therapy is the rule
Bipolar disorder can be difficult to treat, especially in the manic phase, because elevated feelings of well being confuse patients about the severity of their illness. Agents used to treat bipolar disorder include mood stabilizers such as lithium carbonate, valproate, carbamazepine, lamotrigine and atypical antipsychotics. Monotherapy is preferred whenever possible, but combination therapy may be utilized for patients who remain symptomatic on monotherapy or who experience rapid cycling. To maintain euthymia, long term therapy for many patients consists of a combination of medications including a mood stabilizer with an antipsychotic or an antidepressant. Recent guidelines have recommended that antidepressants be used cautiously in bipolar disorder because of their risk of inducing mania. Because the natural history of the disorder involves recurrent episodes, lifetime therapy is the rule.
Treatment and Prophylaxis of Bipolar Disorder with Lithium Carbonate

Onset: 1-2 weeks (consider adjunct therapy to control symptoms during this period) Half-life: Prolonged - up to 40 hours in older adults Dosing: 300-1200 mg/day with food (daily dosing may decrease incidence of adverse effects, especially renal) Therapeutic plasma concentrations 0.4-1.2 mEq/L Renal clearance of lithium is decreased in elderly Adverse Drug Reactions: Fine to coarse tremor, polyuria, hypothyroidism, cardiac effects, nausea, weight gain, fatigue, cognitive impairment, diabetes insipidus, acne Some more frequent at concentrations > 0.8mEq/L Drug-Drug Interactions: Decreased lithium clearance with thiazide diuretics, NSAIDS, ACE Inhibitors, theophylline, tetracycline, metronidazole Monitoring: ECG, renal function, serum lithium levels, thyroid function, ADRs, response to treatment
Treatment and Prophylaxis of Bipolar Disorder with Lithium Carbonate
Lithium is an effective mood stabilizer for bipolar disorder in many elderly patients. Due to the high occurrence of comorbid medical diseases and multiple medications in this population, geriatric patients receiving lithium must be carefully monitored for signs of toxicity. Even minor changes in fluid balance, such as dehydration associated with a minor respiratory illness, can significantly decrease lithium clearance and result in toxicity. The elderly are especially sensitive to the numerous adverse effects of lithium, which include tremor, hypothyroidism, and nausea. The elderly may also be more susceptible to impaired cognition and delirium, with evidence of neurotoxicity that can last for weeks following discontinuation and undetectable serum levels. For many patients, the effective range for prophylaxis is zero-point-four to less than one-pointzero milliequivalents per liter. It is important to note that lithium's antimanic effect may not occur for one to two weeks after therapeutic serum levels are attained. During this period, benzodiazepines and/or antipsychotics may be used adjunctively to achieve symptom control. Drugs that decrease lithium clearance or increase serum levels of lithium carbonate are shown on your screen.
Treatment and Prophylaxis of Bipolar Disorder with Valproate

Dosing: Initial: 5-10 mg/kg/day in divided doses Loading dose: 20 mg/kg/day decreases time to response Titrate to therapeutic plasma concentrations 50-120 mcg/mL, increase every 2-3 days Contraindications: hepatic disease / dysfunction Adverse Drug Reactions: GI upset, thrombocytopenia, nausea, dizziness, somnolence, hyperammonemia, ataxia, tremor, weight gain Drug-Drug Interactions: Valproate increases carbamazepine levels Carbamazepine decreases valproate levels Increased bleeding time with warfarin and aspirin Additive sedation with other sedative agents Monitoring: serum drug levels, ADRs, response to treatment Given concerns about lithiums tolerability and potential for drug interactions in the elderly, valproate is a viable alternative to lithium in the treatment of bipolar disorder. Therapeutic plasma concentrations are noted here. The elderly may not tolerate plasma levels above eighty micrograms per milliliter. This agent is contraindicated in patients with hepatic disease or dysfunction. Common adverse effects of valproate include gastrointestinal upset, thrombocytopenia, nausea, dizziness and somnolence. Interactions with carbamazepine result in higher carbamazepine and lower valproate levels. Valproate also prolongs bleeding time when administered with warfarin or aspirin. All patients on valproate therapy should be monitored for therapeutic response and adverse effects.
Treatment and Prophylaxis of Bipolar Disorder with Carbamazepine (CBZ)

Dosing: Initial: 50-100mg/day in divided doses, titrate to effect Usual range: 300-1200mg/day in divided doses Plasma concentrations: 4-12 mcg/ml as guideline Induces own metabolism up to 30 days after dose change Adverse Drug Reactions: GI upset, rash, benign leukopenia (common), aplastic anemia (rare), sedation, ataxia, SIADH Drug-Drug Interactions: CBZ induces oxidative metabolism of many drugs CBZ metabolism inhibited by CYP450 3A4 inhibitors CBZ levels increased by valproate Additive sedation with other sedative agents Monitoring: serum drug levels, ADRs, response to treatment
Carbamazepine is another alternative for the treatment of bipolar disorder. Plasma concentrations correlate poorly with response, but are used as a guideline. The elderly may not tolerate levels more than eight micrograms per milliliter. Carbamazepine induces the oxidative metabolism of many other medications, which may result in lower than expected levels of concurrent medications and subsequent treatment failure. Common adverse effects of carbamazepine include GI upset, sedation, and benign leucopenia. Carbamazepine induces the metabolism of many drugs, and is inhibited by CYP450 3A4 inhibitors. Levels of carbamazepine are increased by valproate. Patients should be monitored for therapeutic response and adverse effects.
Treatment and Prophylaxis of Bipolar Disorder with Lamotrigine

Dosing: Usual range: 50 200 mg/day Begin 25 mg daily x 2 weeks, increase in 25 mg increments every 2 weeks thereafter If concurrently on valproic acid, begin 25 mg every other day, and increase by 25 mg every 2 weeks thereafter If concurrently on carbamazepine, begin 50mg daily for 2 weeks, increase by 25 or 50 mg daily increments every 2 weeks thereafter Common Adverse Drug Reactions: Headache, nausea, dizziness, ataxia, somnolence, rhinitis, rash Monitoring: ADRs. Neither blood levels or routine lab monitoring are currently recommended Another anticonvulsant with mood-stabilizing effects is lamotrigine. Lamotrigine has been shown to be effective in controlling rapid cycling and mixed bipolar states in people who have not received adequate relief from lithium, carbamazepine and/or valproate. It also appears that lamotrigine has significantly more antidepressant potency than either carbamazepine or valproate. While it is not recommended for the treatment of acute mania, it is considered to be an excellent option for bipolar depression. Initiation of dosing varies depending on the concurrent prescription of other drugs such as carbamazepine or valproic acid. Specific dosing recommendations are provided on the screen. The side-effect of lamotrigine that most often causes the drug to be discontinued is a rash. Rashes can be mild, similar to slight sunburn, or can be quite severe such as Stevens - Johnson syndrome and toxic epidermal necrolysis. The more severe the rash the less likely it is that the individual will be able to continue the medication. A rash is more likely to develop when the initial doses of lamotrigine are high or when lamotrigine is too rapidly started when someone is taking valproate.
Treatment and Prophylaxis of Bipolar Disorder with Atypical Antipsychotics

Agents: Risperidone (Risperdal) Olanzapine (Zyprexa) Clozapine (Clozaril) Quetiapine (Seroquel) Ziprasidone (Geodon) Aripiprazole (Abilify) Combination product of olanzapine and fluoxetine (Symbyax) Recommended use: As monotherapy or adjuvants to prototypical therapies in patients with bipolar disorders and psychoses Adjust doses accordingly to response and/or adverse drug reactions Adverse drug reactions (incidence varies by drug): Somnolence Dizziness Extrapyramidal symptoms Weight gain Glucose dysregulation Lipid abnormalities Elevation in prolactin Dry mouth
Treatment and Prophylaxis of Bipolar Disorder with Atypical Antipsychotics

BLACK BOX WARNING: All of the atypical antipsychotics received a black box warning for increased mortality compared to placebo in geriatric patients. Main causes of deaths in these patients were cardiac-related or infection-related. Clozapine: Agranulocytosis, sudden cardiac death, somnolence, hypotension and anticholinergic effects limit clozapine to the treatment of refractory psychotic mania
Antipsychotics have been shown to be effective as monotherapy or in combination with prototypical therapies such as lithium and divalproex for the acute treatment of mania. Certain agents, such as olanzapine and a combination product of olanzapine and fluoxetine have been shown to be an effective treatment in delaying relapse into either mania or depression in patients with bipolar disorder as well as for the acute depressive episodes of bipolar disorder. Atypical antipsychotics have essentially replaced the prescription of typical or conventional antipsychotics such as haloperidol due to fewer neurological adverse drug reactions such as extrapyramidal symptoms and tardive dyskinesia. Atypical antipsychotics, however, are not without side-effects. Metabolic side-effects associated with some of the atypical antipsychotics are a concern for both clinicians and patients. Adverse events related to central nervous system effects, weight gain, and alterations in glucose, lipid, and prolactin levels in patients treated with atypical antipsychotics have been observed. A significantly higher number of cerebrovascular adverse events, including stroke, have been observed in patients receiving risperidone or olanzapine compared to placebo in elderly patients with dementia. Because of the risk of agranulocytosis and other adverse effects such as somnolence and hypotension, clozapine is reserved for patients with treatment-refractory psychotic mania.

For additional information, see: American Diabetes Association; American Psychiatric Association; American Association of Clinical Endocrinologists; North American Association for the Study of Obesity. Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care 2004; 27:596-601. American Psychiatric Association (2002). Practice guideline for the treatment of patients with bipolar disorder (revision). Am J Psychiatry. 159(4 Suppl): 1-50. Chue P, Kovacs CS. (2003). Safety and tolerability of atypical antipsychotics in patients with bipolar disorder: prevalence, monitoring and management. Bipolar Disord. 5(Suppl 2): 62-79. Eastham JH, Jeste DV, Young RC. (1998). Assessment and treatment of bipolar disorder in the elderly. Drugs Aging. 12(3): 205-24. Hirschfeld R, et al. (2003). Guideline watch: practice guideline for the treatment of patients with bipolar disorder, 2nd edition. J Clin Psychiatry 64:53-59.
Sachs GS. (2003). Decision tree for the treatment of bipolar disorder. J Clin Psychiatry. 64(Suppl 8): 35-40. Suppes T, Dennehy EB, Hirschfeld RMA, et al. Texas Consensus Conference Panel on Medication Treatment of Bipolar Disorder. The Texas Implementation of medication algorithms: update to the algorithms for treatment of bipolar I disorder. J Clin Psychiatry. 2005;66:870-886. National Depressive and Manic-Depressive Association

Module 16 - Pharmacotherapy For Psychiatric Disorders

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Geriatric

Pharmacy Review Module 16 Pharmacotherapy for Psychiatric Disorders

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Kristen Meyer, PharmD Drake University School of Pharmacy

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Types of Anxiety Disorders

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Types of Anxiety Disorders

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Generalized Anxiety Disorder (GAD)

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Generalized Anxiety Disorder (GAD)

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Drugs and Medical Conditions Associated with Anxiety

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Signs and Symptoms of Generalized Anxiety Disorder

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Diagnosing Generalized Anxiety Disorder

Treatment of Generalized Anxiety Disorder

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Pharmacotherapy for Generalized Anxiety Disorder

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Treatment of Anxiety Disorders with Benzodiazepines

Discontinuation of Benzodiazepine Treatment

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Drug-Drug Interactions with Benzodiazepines

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Treatment of Anxiety Disorders with Buspirone (BuSpar)

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Drug-Drug Interactions with Buspirone

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Indications for the Use of Antidepressants to Treat Anxiety Disorders

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Indications for the Use of Antidepressants to Treat Anxiety Disorders

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Indications for the Use of Antidepressants to Treat Anxiety Disorders

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Anxiolytic Agents and Approved Indications

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Anxiolytic Agents and Approved Indications

Summary: Selecting Appropriate Drug Therapy for Anxiety Disorders

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Resources and References

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Resources and References

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Epidemiology of Alcohol Abuse in the Elderly

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Etiology of Alcohol Abuse

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Physiological Changes Associated with Alcohol Abuse

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Clinical Presentation of Alcohol Abuse

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