Mood Stabilizers in the Treatment of Bipolar Disorder: High Yield PRITE Review

1. Mood Stabilizers in the Treatment of Bipolar Disorder: High Yield PRITE Review Arunditi Xantus, MD September 14, 2009

2. What comprises “mood disorders”? • Major depressive disorder • Bipolar disorder type I and II • Dysthymia • Cyclothymia • DSM-IV-TR also includes 3 mood disorder research categories • Minor depressive disorder, recurrent brief depressive disorder, and premenstrual dysphoric disorder. • Others • Mood disorder NOS, depressive disorder NOS, SIMD.

3. DSM-IV criteria for major depressive episode • Symptoms present for at least 2 weeks • Depressed mood or anhedonia plus at least four of the following symptoms • Significant change in weight • Sleep disturbance • Psychomotor retardation or agitation • Fatigue or loss of energy • Excessive guilt or feelings of worthlessness • Difficulty concentrating • Recurrent thoughts of death or suicide

4. DSM-IV criteria for manic episode • One week of elevated, expansive or irritable mood (less if hospitalized) • At least 3 of the following (4 if mood is irritable) • Inflated self esteem or grandiosity • Decreased need for sleep • Pressured speech or more talkative • Flight of ideas or subjective sense of racing thoughts • Distractability • Increased goal directed activity or psychomotor agitation • Risk-taking behavior (sexual promiscuity, increased spending)

5. DSM-IV criteria for hypomanic episode • Four days of elevated, expansive, or irritable mood. • At least 3 of the previously mentioned symptoms for mania (4 if mood is irritable) • Key difference from manic episode– • No marked social or occupational dysfunction • Does not require hospitalization • No psychotic features are present

6. DSM-IV criteria for mixed mood episodes • Criteria for both manic/hypomanic episode and major depressive episode are present for one week. • Symptoms cause marked social or occupational dysfunction, require hospitalization, or psychotic features are present. • Subjectively patients experience rapidly shifting mood.

7. Other key terms: rapid cycling • At least four mood episodes within one year. • Mood episodes may be depressive, manic, hypomanic, or mixed. • Patient must be symptom free for at least two months between episodes, or there must be a change in mood to an opposite type of episode.

10. Lifetime prevalence of DSM-IV mood disorders

11. Bipolar I disorder: an overview • Epidemiology • Life-time prevalence ~ 0.5 to 1.5 %. • Male:female ratio 1:1. • First episodes in males tends to be manic, 1st episode in females tends to be depressed. • Higher rates of mood disorders amongst 1st degree relatives. • 70% concordance rate with monozygotic twins.

12. Bipolar I disorder: an overview • Clinical features • 90% of patients w/ a single manic episode will have a recurrence • Mixed episodes more likely in younger pts • Episodes increase in freqency with age • Common comorbid diagnoses • Substance abuse • Eating disorders • ADHD • 20% have rapid cycling poorer prognosis • Suicide rate is 10-15%

13. Bipolar I disorder: treatment overview • Traditional mood stabilizers • Antidepressants • Must be used with mood stabilizer • TCAs and SNRIs = higher incidence of induced mania • May induce rapid cycling • Atypical antipsychotics • Benzodiazepines • ECT– for depressive or manic episodes • Psychotherapy • Aim is to increase insight to consequences of manic behavior

14. Treatment of bipolar disorder: APA practice guidelines (2002) • Acute treatment • Manic or mixed episode • First line = lithium or valproate + antipsychotic • For less ill patients monotherapy with lithium, valproate or antipsychotic (olanzapine*) • Mixed episodes = valproate over lithium • Benzodiazepines (short term) • Antidepressants should be d/c if possible • If first line med fails, add another first line med • ECT

15. Treatment of bipolar disorder: APA practice guidelines (2002) • Acute treatment • Depressive episode • First line tx = initiation of lithium or lamotrigine • Antidepressant monotherapy not recommended • Breakthrough depression on first line agent? • First optimize first line agent • Next, add lamotrigine, buproprion, SSRI, venlafaxine, or MAOI • Treatment resisitant ECT

16. Treatment of bipolar disorder: APA practice guidelines (2002) • Acute treatment • Rapid cycling • Identify and treat any underlying medical conditions • hypothypothyroid, drug/alcohol use • Taper antidepressants if possible • Lithium or valproate (valproate!!!) • Alternative = lamotrigine

17. Treatment of bipolar disorder: APA practice guidelines (2002) • Maintenance treatment • Valproate or lithium = best evidence • Lamotrigine, carbamazepine, oxcarbamazepine = alternatives • Antipsychotic should be tapered if not indicated* • Psychosocial intervention– group therapy, therapy that addresses illness management • Maintenance ECT

18. APA Guideline Watch: Practice Guideline for the Treatment of Patients with Bipolar disorder (2005) • Manic or mixed episodes • Multiple studies show atypicals (monotherapy or adjunct) are superior to placebo • All approved except clozapine, asenapine, and paliperidone • Depressive episodes • Olanzapine+ fluoxetine (OFC) superior to olanzapine alone and placebo-- FDA approved • Quetiapine superior to placebo-- FDA approved • Lamotrigine also has favorable evidence

19. APA Guideline Watch: Practice Guideline for the Treatment of Patients with Bipolar disorder (2005) • Maintenance • FDA approved-- olanzapine and quetiapinemonotherapy • Psychosocial • Studies have proved efficacy of • Family-focused therapy • Cognitive therapy • Longitudinal psychoeducational programs (2 years) • Techniques aimed to regulate social rhythms

20. Overview of “mood stabilizers” • Lithium: the classic mood stabilizer • Anticonvulsants as mood stabilizers - Valproic acid - Carbamazepine - Oxcarbazepine/eslicarbazepine - Lamotrigine - Topiramate - Gabapentin • Atypical antipsychotics: not just for psychotic mania • Other agents used in bipolar disorder

22. Lithium: the classic mood stabilizer Indications • FDA approved-- bipolar manic episode and mainatenance. • FDA approved -- children 12 years and older. • Augmentation in depressed patients. • Other clinical uses: schizoaffective disorder, severe cyclothymia, borderline personality disorder, impulse control disorders.

23. Lithium: the classic mood stabilizer Pharmacology • May block inositol-1-phosphatase, leading to interuption of PIP 2nd messenger system. • Excreted by kidneys. Not metabolized in liver!! • Impaired renal function or decrease in fluid or salt intake can lead to toxicity. • Lower doses required in elderly 2nd decreased GFR.

26. Lithium: the classic mood stabilizer Clinical guidelines • First line agent for bipolar disorder. • ~30% will not respond to lithium. * • Screening labs: BMP (BUN/creatinine), TSH, CBC, EKG in patients >40 or with a cardiac history, and urine pregnancy. • Therapeutic response may take 4-6 weeks. • Monitoring: • After 5 days then weekly for the first 2 months then biweekly for the next 2 monthsonce stable, every 3-4 months. • Upward titration until serum level = 0.8-1.2.

27. Lithium: the classic mood stabilizer Clinical guidelines, cont. • Lithium should be d/c 2 days prior to ECT combo can lead to delerium. • Pregnancy: category D • First trimester Ebstein’s anomaly • After first trimester, is the DOC amongst first line agents. • Breastfeeding contra-indicated.

28. Lithium: the classic mood stabilizer Side effects • Common– GI distress, weight gain, fine tremor, and cognitive impairment (“fuzzy thinking”) • Renal • Polyuria with 2nd polydipsia in 20% nephrogenic diabetes insipidus • Rare: nonspecific interstitial kidney fibrosis • Thyroid– hypothyroidism (monitor q 6 months)

29. Lithium: the classic mood stabilizer Side effects • Cardiovascular– T wave flattening (similar to hypokalemia), arrhythmias (rare) • Dermatologic– rash, acne, alopecia, worsens psoriasis • Hematologic—benign leukocytosis • Neurologic—muscle weakness, slurred speech, HAs

30. Lithium: the classic mood stabilizer Lithium toxicity • Usually due to decrease fluid or salt intake, or to increased fluid loss • Sx = n/v, diarrhea, coarse tremor, ataxia, headache, slurred speech, confusion, brisk DTRs, coma, death • Mild-mod toxicity = 1.5-2.0 • Severe = >2.5 • Death may occur at >4.0 mEq/L • Treatment– discontinue lithium, hydrate, Kayexalate or GoLYTELY (decreases GI absorption ) • Most severe cases = hemodialysis*

31. Lithium: the classic mood stabilizer

32. Valproate Indications • FDA approved indications: • Absence seizure, simple and complex • Complex partial epileptic seizure • Manic bipolar I disorder • Migraine, prophylaxis • Seizure, multiple seizure types; adjunct • More effective for rapid- or ultra rapid-cycling and for mixed episodes than lithium. • Other clinical uses: ICD, IED, kleptomania, aggressive behavior in patients with developmental disorders or organic brain lesions.

33. Valproate Pharmacology* • Mechanism of action: neuronal signal transduction through protein kinase C. May also involve GABA. • Metabolism: • Hepatic conjugation, mitochondrial beta-oxidation and other oxidative mechanisms extensive. • P450 system relatively unimportant.  • Elimination– largely renal. • Half life 9-16 hours (bid dosing often required). • Highly protein bound.*

37. Valproate Clinical guidelines • First line agent for bipolar disorder, esp for rapid cycling or mixed mood episodes. • Avoid in patients with pre-existing hepatic or hematologic disease. • Screening labs: CBC, LFTs, and urine pregnancy. • Monitoring: • Serum level: after 3 days then weekly x 1-2 mo  then biweeekly x 2 months then q 3-4 months. • Serum level for adequate symptom relief = 50-125 (usually) • CBC and LFTs after one month, and then quarterly x 1 yr.

38. Valproate, cont. Clinical guidelines • Dosing in elderly: ½ that of younger pts. • Therapeutic response: can take 2-4 wks. • Pregnancy: category D • Should not be used in pregnancy neural tube defects (1-2%) and other birth defects. • Hepatic failure and clotting disorders in infants do not breastfeed.

39. Valproate Side effects • Common: sedation, dizziness, n/v • Hepatitis: • Can be lethal, occurs more often in children, usually w/in first 6 months, sx = n/v, lethargy, jaundice, and weakness. • Occurs in 0.0005%; d/c immediately. • 25% will have transient increase in LFTs; monitor! • Pancreatitis: rare, occurs early in treatment. • Hematologic: thrombocytopenia and platelet dysfunctions bleeding disorders.

40. Valproate Side effects, cont. • Neurologic: tremor, ataxia, HA, insomnia, agitation. • Other GI: changes in appetite, wt gain, diarrhea, constipation. • Dermatologic: alopecia, hirsutism, changes in facial features, maculopapular rash. • Overdose: symptoms include somnolence, heart block, and coma.

41. Valproate Other drug-drug interactions • Valproate can displace warfarin from protein binding– monitor carefully! • Valproate inhibits the metabolism, leading to higher serum levels of • Lamotrigine • Ethosuxamide • Diazepam • AZT

42. Valproate

43. Carbamazepine (Tegretol) • FDA approved indications: • Bipolar I disorder, acute manic and mixed episodes • Epilepsy, partial, generalized, and mixed types • Glossopharyngeal neuralgia • Trigeminal neuralgia • Other uses: cyclothymia, schizoaffective disorder, aggression, impulsivity, personality disorders, adjunct in depression. • May be used alone or in combination with lithium.

45. Carbamazepine (Tegretol) • Mechanism of action: largely unknown. • Bind to voltage-dependent sodium channels in inactive state prolonged inactivation 2nd inactivation of Ca++ channels decreased synaptic transmission. • Metabolism: via P450 cytochrome 3A4. Induces its own metabolism. • Excretion: renal, including active metabolites. • Half-life: 25-65 hrs  after 2 weeks, 12-17 hrs.

47. Carbamazepine (Tegretol) Clinical guidelines: • Avoid in patients with liver, cardiac, hematologic abnormalities, as well as renal dysfunction. • Monitoring • Initial: BMP (BUN/Cr), LFTs, EKG in >40 or with cardiac abnl, u preg. • Serum levels: at Day 5 then weekly x 1-2 mo then biwekly x 2 mo then q 3-4 months (serum level 8-12) • Check LFTs, renal function, CBC, and electrolytes after one month, than q 3 months.

48. Carbamazepine (Tegretol) Clinical guidelines: • Lithium nonresponders: can add carbamazepine, and if effective slowly d/c lithium. • Pregnancy: category D • Assoc w/ spina bifida and minor craniofacial abnls. • Although excreted in breastmilk, considered safe in breastfeeding by AAP.

49. Carbamazepine (Tegretol) Side effects • Common: • GI: n/v, diarrhea, constipation, loss of appetite • CNS: sedation, dizziness, ataxia, confusion • Hematologic: • Can cause a life-threatening thrombocytopenia, agranulocytosis, and aplastic anemia in 0.0005%. • Signs of bleeding abnl +/- infx?  CBC immediately! • D/c if WBC < 3,000, ANC <1500, or platelets <100,000. • Hepatic: Hepatitis, cholestatic jaundice.

50. Carbamazepine (Tegretol) Side effects • Dermatologic: rash and uticaria (common), photosensitivity (rare), SJS ( very rare) • Cardiac: AV conduction defects, arrhythmias, CHF • Endocrine: SIADH with resulting hyponatremia • Toxicity: Confusion, stupor, motor restlessness, dilated pupils, tremor, athetoid movements, n/v