Bipolar Disorder
Bipolar I = Mania + Depression
- Bipolar II = Hypomania + Depression
- Cyclothymia = Chronic mild fluctuation between depression and elation
Problems
Untreated >
- Lose about 9 years of life
- 14 years of effective activity
- 12 years of normal health
- 1/5 - 1/4 commits suicide
Mechanism
In manic state - believed to be related to epilepsy and explosive behavioral disorders
So, treatment is directed to control the GABA and Glutamate activities
Antidepressants are used for acute and/or prophylactic treatment - with the lowest effective dose for the shortest time
Medications
Mood stabilizer
Lithium
Carbamazepine (Tegretol)
Valproic acid (Depakote)
Gabapentin (Neurontin)
Lamotrigine (Lamictal)
Medications
Other possible drugs under investigation
Topiramate (Topamax)
Tiagabine (Gabitril)
Clozapine
Olanzapine
Risperidone
Donepezi (Apricept)
Omega-3 Fatty Acids
Lithium
Pharmacokinetics
- absorbed rapidly and completely within 8 hours
- Peak blood level within 3 hours
- cross blood brain barrier slowly and incompletely
- mostly excreted unchanged by the kidneys
- half-life within 18 to 24 hours
Lithium
Pharmacodynamics
unclear
possible routes
affect nerve membranes
affect receptor systems
intracellular second-messenger
induce alteration of specific genes
Lithium
Side Effects
- narrow effective dose (0.5 - 0.7 mEq/L)
- below 0.5 - no therapeutic effect
- about 1.0 - mild toxic effect
- above 2.0 - severe and potentially fatal
Lithium
Side Effects
e.g. nausea, vomiting, diarrhea, abdominal pain, tremor, lethargy, impaired concentration, dizziness, slurred speech, ataxia, muscle weakness, nystagmus, obesity, thyroid enlarged, rashes, renal impaired, difficulty with memory and cognitive functioning, seizure, cardiac arrhythmias, coma, death.
Lithium
Side Effects
Teratogenic - malformation of cardiovascular system
lead to noncompliance (~50%)
stop taking > worse than never have taken the drug > high recurrent, 14x increase attempt suicide, 13x completed
Lithium
Treatment for overdosage
nonspecific
stop taking the drug
infuse sodium-containing fluid
hemodialysis, gastric lavage, diuretic therapy, antiepileptic medication
recovery takes weeks or months
Carbamazepine
Better than lithium in correcting rapid-cycling bipolar disorder
Better than lithium in treating nonclassical bipolar cases
Therapeutic plasma levels - 5 to 10 micrograms per milliliter
Can be used in combination with lithium
Carbamazepine
Side Effects
e.g. gastrointestinal upset, sedation, ataxia, visual disturbances, dermatological reactions, modest detrimental effects on cognitive functioning, leukopenia, aplastic anemia
teratogenic - 1% develops neural tube defect (supplement of folic acid may reduce the risk)
Carbamazepine
Tolerance
- induce the drug-metabolizing enzymes (e.g. CYP-3A4) in the liver
Valproic Acid (Valproate)
Mechanism
increase GABA synthesis and release
reduce the release of the epileptogenic amino acid gamma-hydroxybutyric acid
attenuate neuronal excitation induced by NMDA-type glutamate receptors
effects on gene expression in critical brain circuits
exerts direct effects on excitable membranes (unsure)
Valproate
Better than lithium in treating acute mania, rapid-cycling bipolar disorder, and cyclothymia
- can be used in combination with lithium
Valproate
Side Effects
e.g. GI upset, sedation, lethargy, hand tremor, alopecia (lose of hair), metabolic changes in liver, cognitive dysfunctioning
in females - starting before 20 > 8% develops obesity, polycystic ovaries, increase levels of serum androgens
teratogenic
But better than others for nursing mothers
Gabapentin (Neurontin)
A primary drug as an anticonvulsant
- No FDA approval for treating Bipolar Disorder
Gabapentin
Good pharmacokinetic features
not bound to plasma proteins
not metabolized
excreted unchanged through kidneys
few pharmacokinetic drug interactions
does not alter kinetics of lithium (good choice for combination therapy)
absorbed by a saturable active transport mechanism
half-life within 5 to 7 hours
Gabapentin
Side Effects (tolerable)
e.g. sleepiness, dizziness, ataxia, nystagmus, double vision, dry mouth, nausea, flatulence, reduced libido
Lamotrigine (Lamictal)
Pharmacokinetics
absorbed rapidly and completely
with little first-pass metabolism (98% reaches plasma)
peak plasma concentration within 1 to 5 hours
55% protein bound
metabolized before excretion
half-life within 26 hours
Lamotrigine
Pharmacodynamics
- Full understanding - unclear
inhibit the release of excitatory neurotransmitter glutamate
Lamotrigine
Some features
effective in patients refractory to other drugs
less than topiramate in causing adverse cognitive effects
drug interactions
with Valproate > half-life doubles
with Carbamazepine > half-life shortens
with Gabapentin > acts independently in treating pain states
Lamotrigine
Side Effects
- e.g. dizziness, tremor, headache, nausea, rash (can be serious particularly in adolescents, death reported)
Other Drugs
Topiramate (Topamax)
primary an anticonvulsant
effective for bipolar disorder as an adjunctive agent
Side Effects:
weight loss (counter-effect to lithium and valproate)
tingling in the extremities, irritability, anxiety
worse than gabapentin and lamotrigine in producing cognitive depression
Other Drugs
Tiagabine (Gabitril)
- a GABA reuptake inhibitor
- effective in treating bipolar disorder in some studies
Other Drugs
Clozapine
an atypical antipsychotics
more antimanic than antidepressant
Side Effects (serious):
sedation, weight gain, withdrawal, constipation, agranulocystosis, urinary incontinence, hypotension, esophagitis, seizures, excessive drooling
Other Drugs
Olanzapine
- an atypical antipsychotics
- 1st antipsychotic drug gained FDA approval for short-term treatment of acute mania
Other Drugs
Risperidone
- an atypical antipsychotics
- reported effective in treating bipolar disorder, but requires further investigation
Other Drugs
Donepezil (Aricept)
- an acetylcholinesterase inhibitor
- primarily used for Alzheimer’s disease
Other Drugs
Omega-3 Fatty Acids
- obtained from marine or plant
- known to inhibit neuronal signaling transduction systems
Other Drugs
Benzodiazepines
- e.g. clonazepam and lorazepam - effective in treating acute mania (but less effective than IV loaded valproate)
Other Drugs
Clonidine
an antihypertensive drug
decrease release of NE
tried in refractory patients
effectiveness remains unproven
Verapamil and Calcium channel blockers
effectiveness remains questionable
Psychotherapeutic and psychosocial treatments
- reduce distress and improve functioning between episodes and to decrease the frequency and intensity of future episodes
Psychotherapeutic and psychosocial treatments
Range of treatment
emotional consequences of periods of major mood disorder and diagnosis of a chronic mental illness
developmental deviations and delays caused by past episodes
problems associated with stigmatization
problems regulating self-esteem
fears of recurrence and consequent inhibition of normal psychosocial functioning
Psychotherapeutic and psychosocial treatments
Range of treatment (cont.)
interpersonal difficulties
marriage, family, childbearing, and parenting
academic and occupational problems
other legal, social, and emotional problems that arise from reckless, violent, withdrawn or bizarre behavior that may occur during episodes
Psychotherapeutic and psychosocial treatments
Conditions
provided that the above conditions are not the result of:
medications such as antidepressants, caffeine, behaviroral stimulants (e.g. cocaine), etc.; or
disease such as thyroid hyperactivity
Psychotherapeutic and psychosocial treatments
Examples of psychotherapy
Cognitive-behavioral therapy
Psychodynamically oriented therapy
Family therapy
Couples therapy
Interpersonal psychotherapy
Self-help groups
Psychotherapeutic and psychosocial treatments
- Combination of drug and psychotherapy
- believed to be the most effective treatment for bipolar disorder
Prepared by
Mary, Angela, Tze