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. 1949- 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 18-24 hrs,rest within 1-2 wks

Recommended .75-1.0 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 2nd 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: 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, 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

Thank You