Drugs Used to Treat Bipolar Disorder

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

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

Mania vs. Depression:Treatment options  Manic Episode- anti-psychotics (ex. Zyprexa), or benzodiazepines (sedating)  Depressive Episode- temporary co- administration with antidepressants  As a whole- mood stabilizers, classically- Lithium. 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  1920’s- used as a sedative, hypnotic, and anti-convulsant  1940’s- investigated as a salt substitute for heart disease patients -How did this work out? - Poorly- many people died from toxicity - The Doctors decided that maybe it wasn’t such a good idea

History Cont.  experiments with animals led to lethargy, and use for acute mania.  The logic was simply to make them too tired to run out and repaint the entire house, have wild sex and go shopping  This is where non-compliance fits in (seen in up to 50% of patients)… 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

So where does this leave us?  Since its discovery, Lithium has been found to be superior to placebo  In recent years though, efficacy is being questioned: -Long term results not as good as expected -28% discontinue use, 38% experience relapse on the drug *Even so, it is widely prescribed, demonstrates considerable efficacy, and reduction in mortality risks

Pharmacokinetics:  Peak blood levels reached in 3 hrs, fully absorbed in 8 hrs  Absorbed rapidly and completely orally  Efficacy correlates with blood levels  Crosses blood-brain barrier slowly and incompletely  Usually taken as a single daily dose

Kinetics Cont.  Approx. 2 wks to reach a steady state within the body  ½ of oral dose excreted in hrs,rest within 1-2 wks  Recommended mEq/L, optimum would be.5-.7 mEq/L, with 2 mEq/L displaying toxicity  Metabolized b/f excretion

Important:  Because of its resemblance to table salt, when Na+ intake is lowered or loss of excessive amounts of fluid occurs, blood levels may rise and create intoxication

Pharmacodynamics  No psychotropic effect on non-Bipolars  Affects nerve membranes, multiple receptor systems and intracellular 2 nd messenger impulse transduction systems.  Interacts with serotonin  Potential to regulate CNS gene expression, stabilizing neurons w/ associated multiple gene expression change.

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 neuron’s response to synaptic input, and therefore stabilizing the membrane

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 anti-epileptics may demonstrate better protection against relapse, greater therapeutic efficacy, and studies support this as a rule vs. an exception

Illegal Drug Use  More than 55% of Bipolar patients have a history of drug abuse  Some abuse might occur before the first episode, or after diagnosis  Used by some as a way to self-medicate

If Lithium Doesn’t 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 anti-manic 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: 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, Borderline Personality, 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

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  May include cognitive behavioral, psychodynamically oriented, family, couples, interpersonal, and self-help group therapies

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