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Anxiety Disorders & Anxiolytics
Fear & Anxiety
 Fear: An adaptive response to threatening situations. Innate & species-specific. Learned.
 Anxiety disorders: Caused by inappropriate expression of fear
 Anxiety disorders involve the inappropriate expression of fear.
 Anxiety disorders are the MC group of psychiatric disorders (~ 15% of population, cost to US ~42 billion $/year).

Types of anxiety:
 Generalized anxiety disorder (GAD): chronic anxiety, exaggerated worry with little or nothing to provoke it.
 Panic disorder: unexpected episodes of intense fear with autonomic nervous system activation.
 Obsessive-compulsive disorder: recurrent, unwanted thoughts (obsessions) & repetitive behaviors (compulsions).
 Social phobia: overwhelming self-consciousness in public that prevents normal function.
 Post-traumatic stress disorder: prompted by severe trauma & causing episodes w/ a sense of reliving part of event.

General Anxiety Disorder (GAD) Diagnosis

 Excessive worry over every day problems lasting for at least 6 months
 Defining symptoms = Restlessness, Fatigue, Irritability, Insomnia, Distractibility & Muscular tension
 Important to distinguish anxiety disorders from underlying problems

GAD Symptoms

Behavioral testing for determination of anxiety state in animal model

 Light-dark box
- Rodents favor dark environment
- Percentage of time in the dark indicates emotional state
- Anxiolytics should increase the percentage of time spent in the light
 Elevated plus maze
- Two open arms and two closed arms
- Rodents tend to spend more time in closed arms
- Anxiolytics should increase the percentage of time spent in the open arms.

Neuroanatomy of anxiety
 Amygdala: the amygdala is recognized as one of the central areas for anxiety and fear responses. Lesions of
amygdala almost completely abolish anxiety and stimulation of the amygdala elicits anxiety.
 Hippocampus: This structure is now well established as key region for learning and memory. Emotional responses
require recall of previous experiences, which may involve hippocampal circuits.
 Hypothalamus: the hypothalamus is the region that is capable of eliciting a coordinated expression of emotions
including the autonomic, behavioral and hormonal responses that accompany emotional states.
 Midbrain central gray: This is another important structure in the efferent pathway from the higher limbic
structures. Both the central gray and the hypothalamus also project back to the higher centers and are capable of
eliciting emotional states.
 Locus coeruleus: The locus ceruleus has norepinephrine cell bodies that project to nearly all the CNS. The
norepinephrine fibers have a complex function modulating the activity of the local neurons in many of the
emotional processing centers. Stimulation of the locus itself can cause anxiety-like responses and bring about
autonomic changes.
 Raphe nuclei: These contain the serotonin cell bodies that project fibers to most the CNS. Similar to
norepinephrine, the serotonin fibers also have a modulatory function.
 Cortex (temporal/frontal): Many areas of the neocortex are specifically involved in emotional responses. The
prefrontal cortex and some areas of the temporal cortex are particularly implicated.
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Neuronatomical Circuits
 Structures listed in previous slides form a complex circuit that generates & regulates emotional responses (anxiety)

Neurotransmitter systems
 GABA-benzodiazepine complex: The GABA-A receptor molecule is associated with Cl- channels and serves an
inhibitory function.
 Excitatory amino acids: the excitatory amino acid (glutamate) receptors are also implicated in anxiety regulation.
NMDA receptor is important in learning and memory processes by its role in regulating synaptic plasticity.
 Norepinephrine: norepinephrine is an important modulator of neuronal function.
 Serotonin: serotonin modulates also the neurons of the limbic system. Serotonin and norepinephrine function in a
mutually balancing manner in many limbic areas.
 Corticotrophin releasing hormone (CRH): CRH is a peptide that has a key role in regulation of stress and related
emotional disturbances such as anxiety and depression.
 Cholecystokinin (CCK): CCK is another peptide implicated in anxiety.
 Neuropeptide Y (NPY): = another peptide expressed in limbic areas & may have a function in anxiety regulation.

Biological bases of anxiety disorders

 Components of the stress response: avoidance behavior, increased
vigilance and arousal, activation of sympathetic ANS, release of
cortisol [mediated by the hypothalamic-pituitary-adrenal axis (HPA)].
 Parvocellular neurosecretory neurons in the hypothalamus
→ release of corticotropin-releasing hormone (CRH)
→ adrenocorticotropic hormone (ACTH)
→ cortisol

Activation of the amygdala stimulates the HPA axis.

 Activation of the hippocampus suppresses the HPA axis.
Glucocorticoid receptors in the hippocampus respond to cortisol and
the hippocampus suppresses CRH release from the hypothalamus.

 Amygdala and hippocampus have opposite effects on the stress response. Over-activation of the amygdala or
under-activation of the hippocampus can lead to an excessive activation of the HPA system.
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Hypothalamic-pituitary-adrenal (HPA) axis
normal person

Hypothalamic-pituitary-adrenal (HPA) axis in anxiety/depression

Conditions Evoking Anxiety

 Cardiovascular problems = Symptoms include angina, arrhythmias, hypertension, valvular disease
 Diet = Caffeine, vitamin deficiencies
 Drugs = Akathisia (antipsychotics), Stimulants (cocaine, amphetamines). CNS depressant withdrawal
 Metabolic disorders = Cushing's disease (hormone disorder caused by high levels of cortisol in the blood),
hyperthyroidism, hypoglycemia, menopause, porphyria (heme is not made properly)
 Hematological abnormalities = Anemias
 Neurological problems = Encephalopathies, seizure disorders
 Respiratory pathology = Asthma, Chronic obstructive pulmonary disease (COPD)
 Tumors = Insulinoma (tumor of the pancreas), pheochromocytoma (rare tumor of adrenal gland tissue)
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Recurrent unexpected panic attacks
 Discrete period of intense fear or discomfort.
 Associated symptoms (at least 4) develop suddenly within 10 minutes:
- Palpitations, pounding heart, or accelerated heart rate
- Sweating; trembling or shaking; sensations of shortness of breath or smothering; feeling of choking.
- Chest pain or discomfort; nausea or abdominal distress; feeling dizzy, unsteady, lightheaded, or faint.
- Derealization (feelings of unreality) or depersonalization (being detached from oneself); fear of losing control
or going crazy; fear of dying.
- Paresthesias (numbness or tingling sensations); chills or hot flushes.

Obsessive compulsive disorder (OCD):

 = a severe neuropsychiatric disorder characterized by recurrent, intrusive thoughts/images (obsessions) and
repetitive, ritualistic behaviors (compulsions) that are distressing and embarrassing to the patient.
 OCD begins in adolescence and early adulthood.
 OCD appears to have a genetic predisposition.
 Functional imaging and pharmacological studies have shed some light on the mechanisms underlying this disorder.

Neuroanatomy of OCD = Several anatomical structures are implicated in the development of OCD.
 Striatum (caudate + globus pallidus): the involvement of striatum was
based on findings that many disorders of the basal ganglia such as
Tourette’s syndrome & sydenham’s chorea were associated w/ OCD.
- PET studies have shown  caudate metabolism in OCD.
 Orbitofrontal cortex: this area is critical in risk assessment & decision
making. PT w/ OCD exhibit metabolic activity in this region.

Neurotransmitters in OCD
 Serotonin: serotonin is frequently implicated in the development of the symptoms of OCD. Selective serotonin
reuptake inhibitors (SSRIs) are effective in treating OCD.
 Dopamine: there is a significant overlap between OCD and Tourette’s syndrome, an illness that is linked to
dopamine abnormality in the striatum. OCD patients with tic disorder (another dopamine related movement
disorder) respond better when SSRIs are augmented with antipsychotic drugs that are dopamine receptor
 Neuropeptides: Patients with OCD show increased cerebrospinal fluid (CSF) levels of vasopressin. Similarly, CSF
oxytocin levels have also been reported to be abnormal in OCD.

Therapeutic Strategies
 Remove underlying cause
 Treat psychiatric disorder
- Depression  SSRI
- Psychosis  antipsychotics
 Situational anxieties should not be treated with medications
 Non-drug treatments: Psychotherapy; Relaxation techniques; Meditation; Hypnosis; Prayer
 Generalized anxieties can be effectively managed with drugs
- Acute anxieties = Perhaps due to stress or illness, Effectively treated with anxiolytics
- Chronic anxiety (> 4 weeks) = Treat with anxiolytics combined with psychotherapy

Treatments for anxiety disorders

 Psychotherapy:
- cognitive behavioral therapy,
- relaxation therapy,
- lifestyle changes.
 Pharmacological therapies:
- barbiturates,
- benzodiazepines (anxiolytics) &
- serotonin selective reuptake inhibitors (antidepressants)
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Mechanism of action of benzodiazepines
 Facilitate GABA action at GABAA receptors
 GAD (glutamic acid decarboxylase)
 Termination of GABA actions – reuptake (neuronal and non-neuronal)
 GABA receptor subtypes:
- GABAA receptors: coupled to Cl- channels, hyperpolarization due to Cl- influx
- GABAB receptors: insensitive to benzodiazepines.
 Alcohol (ethanol) has anxiolytic effects, through similar mechanisms.

Serotonin-selective reuptake inhibitors (SSRIs)

 Prozac = fluoxetine, Zoloft = sertraline, Paxil = paroxetine. Celexa = citalopram.
 SSRIs prolong the actions of serotonin by inhibiting their reuptake,
- e.g. from terminals of serotonergic neurons of the diffuse modulatory system.
 Therapeutic effects of SSRIs are due to a slow adaptation of the brain to elevated serotonin levels, including an
increase of glucocorticoid receptors in the hippocampus.

 Barbiturates have been used in the treatment of anxiety  Significant anxiolytic activity
 Factors limiting use =
- Low margin of safety,
- High abuse potential,
- Physical dependency,
- Abstinence syndrome,
- Drug interactions

 Binding sites for GABA: between α1 and β2

 Binding pocket of BDZ: between α1 and γ2
 Barbiturates bind to multiple isoforms of GABAA receptor but at different sites from BDZ

Absorption, metabolism and excretion:

 Absorption: oral, rectal, intravenous, intramuscular
 Protein binding: correlated with lipid solubility
 Metabolism: hepatic microsomal enzymes
 Renal excretion: phenobarbital and conjugated barbiturate metabolites

Drug interactions:
 Synergistic CNS depression with other CNS depressants
 May displace other bound drugs in plasma
 Induces hepatic microsomal enzymes, may increase metabolism of other drugs

 Tolerance for sedative may be stronger than tolerance for respiratory depression,
 Lethal dose depends on barbiturate pharmacokinetics
 Pupillary constriction or hypoxic paralytic dilatation
 Coma, profound depression of respiration – effect of drug and hypoxia on medullary centers
 Complications: pulmonary edema, renal failure
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 Maintain open airway and respiration
 Monitor blood gases, O2 if hypoxic (mechanical assistance may be needed)
 Gastric lavage
 Sympathomimetic for hypotension

 Sedative and anxiolytic properties
- Chlordiazepoxide (1960)
- Diazepam (1962)
- Flurazepam (1970)
 Benzodiazepine prescriptions
- > 60 million each year. > $0.5 billion. 75 % for anxiety
- 67 % of prescriptions by general practitioners, gynecologists, internists (not by psychiatrists or neurologists)

Relationship between mechanisms of action for benzodiazepines and barbiturates:

 BDZ are allosteric activators of GABA binding; ↑ freq of Cl- channel opening in response to GABA at GABAA
 Barbiturates are also allosteric activators at GABAA, ↑open time of Cl- channel
 Barbiturates can stimulate GABA receptors directly, in the absence of GABA; BDZs cannot

Routes of Administration & Absorption: rate of absorption determines speed of onset

 Oral: generally 1-3hr.; Prazepam (Centrax®) and Oxazepam (Serax®) longer; Diazepam (Valium®) and
Clorazepate (Tranxene®) absorbed relatively rapidly
 IV: Diazepam (Valium®) is not water soluble, propylene glycol is used as a vehicle; Midazolam (Versed®)
- - IS soluble in aqueous vehicle, less irritation
 IM: Lorazepam (Ativan®)
 Protein binding: high in most cases, little competition with other drugs
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Metabolism: no induction of microsomal enzymes
 Most long-acting are dealkylated to active metabolites with long half-lives (see figure)
- Oxazepam (Serax®) & Lorazepam (Ativan®) – inactive metabolites, metabolized directly to glucuronides
 Dealkylation & hydroxylation decrease in elderly, cirrhosis, and acute hepatitis; glucuronidation is unaffected

 +30,000 ER visits due to BDZ annually, few percent died in past, most by ETOH, age, preexisting conditions
- Coma, respiratory depression, acute circulatory failure
- Tx of overdose: support vital functions, similar to barbiturates

Benzodiazepine Anxiolytics
 Diazepam  Valium®
 Chlordiazepoxide  Librium®
 Oxazepam  Serax®
 Clorazepate  Tranxene®
 Alprazolam  Xanax®
 Halazepam  Paxipam®
 Lorazepam  Ativan®

 Modulate ongoing GABA activity
 Increase the frequency of channel opening (Barbiturates open the channel for longer periods of time)
 Hyperpolarize neurons = Anxiolytic activity, Anticonvulsant effects, & Skeletal muscle relaxation

 Twice per day dosing sufficient
 May require more than one week for optimal responses
 Drug accumulation
 Withdrawal symptoms = Anxiety, Insomnia & Seizures

Adverse Effects
 Extension of CNS depressant effects = Drowsiness, Dizziness, Ataxia, Paradoxical excitement (MC in elderly)
 CNS effects enhanced when taken with other drugs = Ethanol, Barbiturates & Antihistamines
 Benzodiazepines produce amnesia
- Midazolam (Versed) = a sedative/anxiolytic & adjunct Tx for inducing anesthesia or other med procedures
- Amnestic properties beneficial in such settings

Benzodiazepines: Withdrawal
 Most common withdrawal symptoms = Rebound anxiety, Insomnia
 Other withdrawal symptoms
- Dizziness, headache, altered taste
- Tinnitus (noise ringing in the ear), palpitations, confusion
- Poor concentration, seizures, irritability
 Symptoms more intense for benzodiazepines with short duration of action

Benzodiazepine Detoxification
 Numerous approaches to detoxification have been tried, including:
- Use of B-blockers
- Treatment with antidepressants
- Enhancing GABA activity (partial agonists, anticonvulsants)
- Flumazenil to reverse GABAA receptor down-regulation
- Other anxiolytics (buspirone)
 Current approaches to detoxification include:
- Loading dose at 40% of daily dose
- Gradual decrease of dose by 10% per day
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Drug Interactions
 Benzodiazepines do not induce liver microsomal enzymes
 Potentiate anticholinergic effects of phenothiazines and tricyclic antidepressants
 Absorption delayed by:
- Food
- Maalox (Magnesium-aluminum hydroxide)
- Gelusil (aluminum hydroxide)
 Benzodiazepines enhance effects of ethanol and other CNS depressants
 Drugs that alter benzodiazepine responses:
- Cytochrome P450 inhibitors (Cimetidine)
- Zolpidem
- β-Blockers
- Disulfiram (with particular significance in treating alcoholic patients)
- Oral contraceptives can also inhibit benzodiazepine metabolism

Other Anxiolytics
 Propranolol (Inderal®)
- β1-adrenergic receptor antagonist
- Useful in the treatment of stage fright
- Decreases symptoms, including sweating, elevated heart rate and blood pressure
- 40 – 240 mg/day recommended dose
 Hydroxyzine (Atarax®)
- Antihistamine
- 50 mg/day recommended dose
- Limited cognitive impairment
- Potential adverse effects on fetus
 Buspirone (Buspar®)
- Azaspirodecanedione
- Chemically unrelated to the benzodiazepines
- Serotonin 5-HT1A agonist
o Mechanisms of action: partial 5-HT1A agonist and weak dopaminergic D2 mixed agonist/antagonist
o Inhibits 5-HT release via stimulation of serotonin autoreceptors
o Displays anxiolytic activity
- Major side effects
o CNS: Dizziness, insomnia, headache
o Peripheral: Nausea, tachycardia, myalgia, paresthesia, skin rash
- Metabolism
o Oxidized to 1-pyrimidyl-piperidine (active metabolite)
o Substrate for CYP3A4
o Grapefruit juice increases Area under plasma concentration time curve (AUC) 10-fold
 Furanocoumarins inhibit CYP3A4
- Elimination
o 2/3 excreted in urine. 1/3 excreted in feces. T1/2 is 2-3 hours

Buspirone Effects
 Relatively few side effects as compared with benzodiazepines
- Less sedating
- No tolerance or dependence
- No withdrawal reactions
- No abuse potential
- No cross tolerance with benzodiazepines
- No interaction with alcohol
- Not fatal in overdose
- No anticonvulsant activity
- No skeletal muscle relaxation