2. Bipolar Disorders

3. Background- Bipolar Disorder  Mood disorder that follows cyclical pattern- episodes of mania and depression  Essential feature- mania or hypomania  Mania (DSM-IV-TR definition)- distinct period of abnormally or persistently elevated, expansive or irritable mood lasting at least one week (or any length of hospitalization required (hypomania less severe –at least 4 days)

4. Expansive-defined Lack of restraint in expressing one's feelings, frequently with an overvaluation of one's significance or importance. Irritable, easily annoyed and provoked to anger.

5. Manic Episodes Manic episodes defined as mild, moderate, or severe Psychotic features may be present in severe episode Onset may be acute brought on by some stressful event or sensory overload Typically require hospitalization (hypomania doesn’t lead to hospitalization)

6. Stage Model-Acute Mania Stage 1(hypomania) *increased psychomotor activity- represents inner tension- shouting to hand-wringing-repetitive *emotional lability (feelings or mood fluctuates often). *euphoria or grandiosity (an inflated appraisal of one's worth, power, knowledge, importance, or identity. When extreme, delusional. *coherent but tangential thinking

7. Stage Model- Mania Stage 2 * increased psychomotor activity * heightened lability * angry/hostile * assaultive/explosive * possible grandiose/paranoid

8. Stage Model- Mania Stage 3 *Frenzied motor activity *Incoherent thought process *disoriented or ideas of reference- e.g., TV announcer speaking to me *Florid psychosis

9. Types 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” Bipolar Disorder unspecified-wastebasket diagnosis

10. Case 13- page 86-87- George M. Review this case…….

11. Selected Stats: Estimated 1 out of 4-5 commit suicide Gender Ratios- Type I about even; Type II women over men Psychotic Features- 47-75 % Onset of illness- range 20-40 years First episode- typically mania for men; depression for females

12. Diagnostic Issues Bipolar when present is typically primary diagnosis. Secondary diagnosis not uncommon but may begin after BPD. For example, alcohol dependence or abuse might come after BPD-effort to slow down.

13. Diagnostic Issues Mania can occur w/ certain med disorders- head trauma, brain tumor, endocrine problem Logically mutually exclusive w/ some disorders-Schizophrenia Recent Hx trumps past Hx- diagnosis as teen may have been anxiety disorder; later major depression; at 27, first mania

14. Course Specifiers Raid Cycling- 4 or more episodes in year (depression, mania, hypomania) w/wo interepisode recovery Seasonal pattern-connection between bipolar disorder and seasonal affective disorder (SAD). People with BPD are more likely to have SAD than the general population. The most common pattern is fall depression and spring hypomania,

15. Etiology- 3 More Popular Models Chaotic Attractor Theory- biochemical defect leads to dysregulation in neurotransmitter synthesis. Kindling Model-cumulative subclinical biochemical changes in limbic system- neurons become more excitable; eventually clinical symptoms appear Dysregulation Theory- mood subject to homeostatic mechanisms- failure here leads to mania or depression

16. 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)

17. Lithium Widely recommended treatment for Bipolar Disorder 60-80% success in reducing acute manic and hypomanic states However… issues of non-compliance medication, side effects, and relapse rate with its use are being examined. Same drugs are used with Bipolar I and II- studies have been inclusive as to which drug might be better for BP II BP II- seems to be more tolerance of “monotherapy” as some think you don’t necessarily need a mood stabilizer- won’t get mood swing. Make judgment case by case.

18. History Of Lithium 1920’s- used as a sedative, hypnotic, and anti-convulsant Used to tx anxiety and seizures 1940’s- investigated as a salt substitute for heart disease patients -How did this work out? - Poorly- many people died from toxicity - idea was abandoned

19. History Cont. 1949- experiments with animals led to lethargy, and eventually came idea for use for acute mania. The logic was simply to make BPers too tired to run to act out: stay up all night, be promiscuous and spend money- show bad judgment This is related to non-compliance (seen in up to 50% of patients)… The patient feels s/he is being denied their fun by taking meds, so they give them up.

20. 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. Did not gain acceptance in US until 1970

21. What’s Up Now? Initial choice for tx of mania (along w/ divalproex- Depakote) and essentially remains so 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 However, now multiple drugs used in combo with Lithium or anticonvulsants: anti-depressants, benzodiazapines, anti-psychotics

22. 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

23. 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

24. 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

25. Pharmacodynamics Little psychotropic effect on non-Bipolars- aside from mild cognitive and motor slowing Affects nerve membranes, multiple receptor systems and intracellular 2 nd messenger impulse transduction systems. Interacts with serotonin

26. 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 apparently to reducing a neuron’s response to synaptic input, and therefore stabilizing the membrane. Term mood stabilizer though used by pros is not an FDA approved term!!!

27. Side Effects and Toxicity Are related to plasma concentration levels, so constant blood monitoring is key- that is why some prescribers prfer Depakote Higher concentrations Of Lithium ( 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 dysfunction, cardiovascular Not advised to take during pregnancy, affects fetal heart development. Lithium demonstrates a narrow therapeutic window- close to toxic dose

28. Dosages  Acute mania 1200-2400 mg daily Serum Level: 0.8- 1.5 mEq/l  Maintenance 600- 1800 mg daily Serum Level 0.6-1.2 mEq/L Dosage reduction after acute stage begins to subside.

29. Selected Side-Effects GI- nausea, vomiting, diarrhea - may indicate Lithium toxicity Nervous System/neuromuscular- headache, muscle weakness, lethargy, fine hand tremor. Subsides for most except 10% Use Inderal- beta blocker to control Worsening of tremor, stupor, confusion- toxicity.

30. Side Effects Renal- Lithium relies only on kidneys for elimination- no liver metabolism Expect polydipsia (inc thirst) and polyuria (inc urination)- maintain hydration Not recommended for those with renal problems. Cause structural changes in kidneys, long- term use….debatable.

31. 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

32. Lithium Benefit Probably due to preventing dopamine receptor during manic phase May also contribute to serotonin production by increasing uptake of tryptophan, a serotonin precursor Tryptophan is an essential amino acid. This means that it must be obtained through the diet in adequate quantities to meet the body's needs..

33. Neuroprotective Factors? It is postulated that mood disorders generally reduce neuron quality and cell volume. Certain neuroprotective substances are purportedly helpful in mitigating these effects. Lithium may increase neuroprotective proteins in the brain.

34. Combination Therapy As suggested earlier, combination therapy- Lithium and anti-epileptics may demonstrate better protection against relapse, greater therapeutic efficacy. Studies support this as a rule vs. an exception Some newer drugs are FDA approved “combo drugs” –Symbyax- combo of active ingredients of Prozac (Fluoxetine) and Zyprexa (Olanzapine)- treats depression and mania

35. Valproic Acid (Depakote) An anti-epileptic, it is probably the most widely used anti-manic drug FDA approved Best for rapid-cycling and acute-mania-especially mixed episodes Like Lithium, one theory of mechanism of action again is increase of protective factors 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

36. Carbamazepine (Tegretol) Superior to lithium for rapid-cycling, regarded as a second-line treatment for mania Side effects may include GI upset, sedation, ataxia, blurred vision and cognitive effects. GI upset can be decreased by taking with food. Can decrease white blood cell count- White blood cells are the major infection-fighting cells in the body. Depakote tolerated slightly better than Tegretol- less CNS effects First-line for mixed episodes

37. Blood Monitoring Blood level monitoring required for Tegretol and Depakote. Weekly and then every 3 months. Toxicity- elevated serum level (overdose) can lead to death Toxic Effects Tegretol- neurologic and cardiac malfunction Depakote- somnolence and coma

38. Neurontin (Gabapentin) Primarily an anti-convulsant, yet also “off label,” or without FDA approval for treatment of Bipolar. Can be used for 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

39. Lamictal-Lamotrigine Newer drug used for BP- FDA approved Good for treatment BP depression Side effects usually lighter CNS, GI and dermatologic 10% get a rash In rare cases, Stevens-Johnson Syndrome is a potentially deadly skin disease that usually results from a drug reaction Sometimes newer ACs prescribed for refractory BP

40. Lamictal-Lamotrigine Can also affect eyes- Diplopia- double vision Reported effective with Bipolar, Borderline Personality, Schizoaffective, Post-Traumatic Stress Disorders Half-Life is 26 hrs. Inhibits neuronal excitability and modifies synaptic plasticity

41. Topamax and Trileptal Two newer anti-convulsants that have potential for use in the treatment of Bipolar disorder Not fully established Topamax has weight loss as a good side-effect. Trileptal is structurally similar to Tegretol but better tolerated

42. Atypical Anti-psychotics No support for use as primary first-line agents 3 types that may be used for BP- Clozapine, Risperidone, and Olanzapine Clozapine is effective, yet not readily used due to potential serious side effects Olanzapine is approved for short-term use in acute mania

43. 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

44. 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

45. 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. Drug compliance monitoring and mood monitoring are an important facet of psychotherapy May include cognitive behavioral, psychodynamically oriented, family, couples, interpersonal, and self-help group therapies