Drugs Used to Treat Bipolar Disorder

By: Dr Satar Ostadhadi

Background Information

Episodes of Mania and Depression Intervention when mood swings are severe, disrupt life of the patient and/or family 4 % population prevalence At least 1 manic,hypomanic,or mixed episode

Types/Common Terms

Bipolar I- Most severe, obscures normal functioning, hospitalization common Bipolar II- Hypomanic,Full manic episodes rare. Depression often still severe Cyclothymia- Milder form of BP II, Bipolar Spectrum Disorder Rapid Cycling- 4 or more episodes in a 12 month period,may not be permanent

Symptoms of Bipolar Disorder

Mania Feeling very high on life Talking rapidly Feeling grandiose Erratic and impulsive actions Delusions and hallucinations (severe) Hypomania Like but less severe that mania Euphoric, energetic and productive No hallucinations or delusions Characterized by an unusually good mood Depression Feeling hopeless, sad or empty Fatigue, energy and concentration loss Thoughts of death or suicide

Causes of Bipolar Disorder

Genetic

Factors (X-Linked) Biological Factors Norepinephrine and Serotonin Levels

PET Scan for serotonin

Person in depressive episode

Healthy individual

Effects:

Estimated 1 out of 4-5 commit suicide from inadequate or no treatment Onset of illness around 25 yrs old and untreated, often results in loss of approx. 9 yrs of life, 14 yrs of activity, 12 of normal health Prime candidates for lifetime treatment express at least 2 episodes of mania Mens first episode tends to be mania, While women tend to have a depressed episode first.

Mania vs. Depression:Treatment options

Manic Episode- anti-psychotics (ex. Zyprexa), or benzodiazepines (sedating) Depressive Episode- temporary coadministration with antidepressants As a whole- mood stabilizers, classicallyLithium. Anti-epileptics are also currently being used ( Tegretol, Depakote, Neurontin, Lamictal)

Lithium

Widely recommended treatment for Bipolar Disorder 60-80% success in reducing acute manic and hypomanic states However issues in non-compliance to take medication, side effects, and relapse rate with its use are being examined in terms of being the best option

History
1920s- used as a sedative, hypnotic, and anti-convulsant 1940s- investigated as a salt substitute for heart disease patients

- Poorly- many people died from toxicity - The Doctors decided that maybe it wasnt such a good idea

History Cont.

1949- experiments with animals led to lethargy, and use for acute mania.

the patient feels they are being robbed of their fun by taking meds, so they give them up.

More On Non-compliance

Other reasons patients refuse meds: -weight gain - less energy, productivity - feel disease has resolved, no longer need medication Relapse rate is high regardless of withdrawal being gradual or acute, suicide risk back up episodes are often worse than original symptoms, so treatment is often life-long

Pharmacokinetics:

Absorption: Readily absorbed from the GI tract. Absorption is not significantly impaired by food. T max is 0.5 to 3 h. Therapeutic serum level is 0.4 to 1 mEq/L. Steady state is reached in 5 to 7 days Distribution: Distribution space of lithium approximates that of total body water. Not protein bound. Distribution across the blood-brain barrier is slow; however, the CSF lithium level is about 40% of the plasma concentration Elimination: About 95% eliminated by the kidney; primarily excreted in the urine. Renal excretion is proportional to its plasma concentration. The half-life is about 24hrs.

Pharmacodynamics

No psychotropic effect on non-Bipolars. Affects nerve membranes, multiple receptor systems and intracellular 2nd messenger impulse transduction systems. The other mechanisms by which lithium might help to regulate mood include the alteration of gene expression and the non-competitive inhibition of an enzyme called inositol monophosphatase.

How does a simple ion do all of this?

Even as a simple ion, it has complex effects on multiple transmitter systems and mood stabilizing attributes

This is due to a latter effect reducing a neurons response to synaptic input, and therefore stabilizing the membrane

It has been discovered that lithium protects neurons by increasing the levels of a neuroprotective protein called Bcl-2. Lithium has been found to help stimulate the production of new neurons (neurogenesis) in the hippocampus part of the limbic system that control emotions and behavior. A major breakthrough came in 2000, with the demonstration that lithium increases the amount of gray matter in the human brain, probably by stimulating the production of a growth promoter called brain-derived neurotrophic factor.

Side Effects and Toxicity

Relate to plasma concentration levels, so constant monitoring is key Higher concentrations ( 1.0 mEq/L and up produce bothersome effects, higher than 2 mEq/L can be serious or fatal Symptoms can be neurological, gastrointestinal, enlarged thyroid, rash, weight gain, memory difficulty, kidney disfunction, cardiovascular Not advised to take during pregnancy, affects fetal heart development

Combination Therapy

Combination therapy with Lithium and antiepileptics may demonstrate better protection against relapse, greater therapeutic efficacy, and studies support this as a rule vs. an exception

If Lithium Doesnt Work

40% of Bipolars are resistant to lithium or side effects hinder its effectiveness Therefore, we must consider alternative agents for treatment

Valproic Acid (Depakote)

An anti-epileptic, it is the most widely used antimanic drug Augments the post-synaptic action of GABA at its receptors (increasing synthesis and release) Best for rapid-cycling and acute-mania Therapeutic blood levels: 50-100 Mg/L Side effects include GI upset, sedation, lethargy,tremor, metabolic liver changes and possible loss of hair Can also be used for anxiety, mood, and personality disorders

Carbamazepine (Tegretol)

Superior to lithium for rapid-cycling, regarded as a second-line treatment for mania Correlation between therapeutic and plasma levels (estimated between 5-10 Mg/L) Side effects may include GI upset, sedation, ataxia and cognitive effects

Gabapentin
Primarily an anti-convulsant, yet also off label, or without FDA approval for treatment of Bipolar and many other anxiety, behavioral and substance abuse problems, possibly pain disorders GABA analogue not bound to plasma proteins, not metabolized, few drug interactions Half-Life is 5-7 hours Side Effects include sleepiness,dizziness,ataxia and double vision

Lamotrigine

Reported effective with Bipolar, Schizoaffective, Post-Traumatic Stress Disorders 98% of administered drug reaches plasma Half-Life is 26 hrs. Inhibits neuronal excitability and modifies synaptic plasticity Side Effects may include dizziness, tremor, headache, nausea, and rash

Topiramate and Tiagabine

Two newer anti-convulsants that have potential for use in the treatment of Bipolar disorder

Atypical Anti-psychotics

3 types that may be used for BP- Clozapine, Risperidone, and Olanzapine

Risperidone seems more anti-depressant than anti-psychotic Clozapine is effective, yet not readily used due to potential serious side effects Olanzapine is approved for short-term use in acute mania

Acetylcholinesterase Inhibitors

Potentiating the action of acetylcholine may exert relief from mania This potentiation is the result of inhibiting the enzyme acetylcholine esterase

Omega-3 Fatty Acids

Obtained from plant or marine sources Known to dampen neuronal signaling transduction systems in a variety of cell systems Being investigated as a treatment for Bipolar Disorder

New Mood Stabilizers

Lamictal Neurotonin Topamax

Have been shown to be effective in adults Effects are not known in children yet Mechanisms are unknown Effects are quicker Side effects appear less May have long term side effects that are not known of yet

Psychotherapeutic and Psychosocial Treatments

Combination drug and psychotherapeutic intervention is the most effective treatment

Goals of Psychotherapeutic treatment are to reduce distress and improve function between episodes

Evidence Based Guidelines for Treating Bipolar Disorder

www.bap.domainwarehouse.com/conse

nsus/FinalBipolarGuidelines.pdf

Thank You