2. MOOD STABILIZER DR.Mohamadbeigi Psychiatrist

3. Bipolar Disorder (Manic-Depressive Illness) Mania: 1 wk of (hypomania 4 days) Mania: 1 wk of (hypomania 4 days) Elevated, Expansive, Irritable Mood +3 (4): Elevated, Expansive, Irritable Mood +3 (4): inflated self-esteem or Grandiosity inflated self-esteem or Grandiosity  need for sleep (rested with <3hrs)  need for sleep (rested with <3hrs)  talkative  talkative Flight of ideas, racing thoughts Flight of ideas, racing thoughts Distractibility Distractibility  goal-directed activity / psychomotor agit.  goal-directed activity / psychomotor agit.  pleasurable activ. w painful consequence (spending, sex, investments)  pleasurable activ. w painful consequence (spending, sex, investments)

4. Bipolar Disorder Depressive episode: 2 wks (5 Total Sx) Depressive episode: 2 wks (5 Total Sx) Depressed (Irritable in kids) Depressed (Irritable in kids) Anhedonia Anhedonia  /  appetite  /  appetite  /  sleep  /  sleep psychomotor agitation /retardation psychomotor agitation /retardation Fatigue /  energy Fatigue /  energy worthless / guilt worthless / guilt  concentration / indecisive  concentration / indecisive suicidal ideation suicidal ideation

5. Bipolar Disorder BP-I: Mania (with/without Depr) BP-I: Mania (with/without Depr) M or M-D M or M-D BP-II: Depression and hypomania BP-II: Depression and hypomania D-m D-m Cyclothymia: m-d Cyclothymia: m-d Mixed episode: M + D (same time) Mixed episode: M + D (same time) Rapid cycling: 4 or more episodes / yr. Rapid cycling: 4 or more episodes / yr.

7. What is a mood-stabilizer? A medication that alleviates the frequency &/or intensity of manic, hypomanic, depressive or mixed episodes in bipolar disorder patients, and does not increase frequency or severity of any of the types bipolar disorder episodes (Bowden C, 1998, Neuropsychopharmacol, 19, 194-199)

8. Mood Stabilizers Lithium Lithium Anticonvulsants Anticonvulsants Valproic Acid Valproic Acid Carbamazepine Carbamazepine New Anticonvulsants : New Anticonvulsants : Lamotrigine Lamotrigine Topiramate Topiramate Gabapentin Gabapentin Antipsychotics Antipsychotics Classic (Haloperidol) Classic (Haloperidol) Novel (Clozapine, Olanzapine) Novel (Clozapine, Olanzapine)

9. lithium Lithium was approved by the US Food and Drug Administration (FDA) for the treatment of mania in 1970, more than 20 years after the first favorable reports by John F. J. Cade, an Australian psychiatrist. It is used for short-term, long-term, and prophylactic treatment of bipolar I disorder. Until recently, it was approved for both acute and maintenance treatment. It is also used as an adjunctive medication in the treatment of major depressive disorder.

10. Pharmacologic Actions Lithium is rapidly and completely absorbed after oral administration. Lithium does not bind to plasma proteins, is not metabolized, and is excreted through the kidneys. The blood brain barrier permits only slow passage of lithium, which is why a single overdose does not necessarily cause toxicity and why long-term lithium intoxication is slow to resolve.

11. Therapeutic Indications Bipolar I Disorder  Manic Episodes  Bipolar Depression  Maintenance Major Depressive Disorder Schizoaffective Disorder and Schizophrenia

12. Adverse Effects of Lithium Gastrointestinal Appetite loss, nausea, vomiting, diarrhea Neurologic Benign, nontoxic : dysphoria, lack of spontaneity, slowed reaction time, memory difficulties Tremor: postural, occasional extrapyramidal Toxic : coarse tremor, dysarthria, ataxia, neuromuscular irritability, seizures, coma, death Endocrine Thyroid: goiter, hypothyroidism, exophthalmos, hyperthyroidism (rare) Parathyroid: hyperparathyroidism, adenoma

13.  Cardiovascular Benign T-wave changes, T-wave inversion, sinus node dysfunction  Renal Concentrating defect, morphologic changes, polyuria (nephrogenic diabetes insipidus), reduced GFR, nephrotic syndrome, renal tubular acidosis  Dermatologic Acne, hair loss, psoriasis, rash  Weight Gain

14. Signs and Symptoms of Lithium Toxicity Mild to moderate intoxication (lithium level = 1.5 to 2.0 mEq/L ) GI: Vomiting,Abdominal pain,Dryness of mouth Neurologic: Ataxia,Dizziness,Slurred speech,Nystagmus,Lethargy or excitement Muscle weakness Moderate to severe intoxication (lithium level = 2.0 to 2.5 mEq/L) GI :AnorexiaPersistent nausea and vomiting Neurologic :Blurred vision,Muscle fasciculations,Clonic limb movements,Hyperactive deep tendon reflexes,Choreoathetoid movements,Convulsions,Delirium,Syncope,Electroencephalogr aphic changes Stupor,Coma Circulatory failure (lowered BP, cardiac arrhythmias, and conduction abnormalities) Severe lithium intoxication (lithium level >2.5 mEq/L) Generalized convulsions Oliguria and renal failure Death

15. Drug Interactions with Lithium Antipsychotics: Case reports of encephalopathy, worsening of extrapyramidal adverse effects, and neuroleptic malignant syndrome; inconsistent reports of altered red blood cell and plasma concentrations of lithium, antipsychotic drug, or both Antidepressants: Occasional reports of a serotonin-like syndrome with potent serotonin reuptake inhibitors Anticonvulsants :No significant pharmacokinetic interactions with carbamazepine or valproate; reports of neurotoxicity with carbamazepine; combinations helpful for treatment resistance NSAIDs May reduce renal lithium clearance and increase serum concentration; toxicity reported (exception is aspirin) Thiazides: Well-documented reduced renal lithium clearance and increased serum concentration; toxicity reported Potassium sparing Limited data, may increase lithium concentration ACE inhibitors Reports of reduced lithium clearance, increased concentrations, and toxicity Calcium channel inhibitors Case reports of neurotoxicity; no consistent pharmacokinetic interactions Metronidazole Increased lithium concentration Methyldopa Few reports of neurotoxicity Propranolol Used for lithium tremor; possible slight increase in lithium concentration

16. Routine Laboratory Monitoring TSH concentrations should be measured every 6 to 12 months. check serum creatinine concentration, and 24-hour urine volume at 6-month intervals Lithium levels should be obtained every 2 to 6 months, except when signs of toxicity are seen, during dosage adjustments, and in persons suspected to be noncompliant with the prescribed dosages. Baseline ECGs are essential and should be repeated annually.

17. Correlates of Relative Lithium Responsiveness Episode characteristics Rapid or faster cycling Episode contiguity Intermittent, that is, with a well interval Sequence pattern Mania → depression → well interval Number of episodes before starting prophylaxis Three or fewer Quality of mania Euphoric Comorbidities History of substance abuse History of anxiety disorder Genetic background Family history of anxiety disorder Family history of bipolar illness and especially lithium response

18. Valproate Valproate or valproic acid, is used for the treatment of acute manic or mixed episodes associated with bipolar I disorder. Other indications include seizure disorder and migraine prophylaxis.

19. valproate is rapidly and completely absorbed 1 to 2 hours after oral administration, with peak concentrations occurring 4 to 5 hours after oral administration. The plasma half-life of valproate is 10 to 16 hours. Valproate is highly protein bound.

20. Therapeutic Indications Bipolar I Disorder Acute Mania Mixed Episodes Acute Bipolar Depression Prophylaxis Schizophrenia and Schizoaffective Disorder Other Mental Disorders

21. Adverse Effects of Valproate Common GI irritation Nausea Sedation Tremor Weight gain Hair loss Uncommon Vomiting Diarrhea Ataxia Dysarthria Persistent elevation of hepatic transaminases Rare Fatal hepatotoxicity (primarily in pediatric patients) Reversible thrombocytopenia Platelet dysfunction Coagulation disturbances Edema Hemorrhagic pancreatitis Agranulocytosis Encephalopathy and coma Respiratory muscle weakness and respiratory failure

22. Recommended Laboratory Tests During Valproate Therapy Prior to treatment Standard chemistry screen with special attention to liver function tests CBC, including white cell and platelet count During treatment CBC and Liver function tests at 1 month, then every 6 to 24 months if no abnormalities are found Liver function test results become abnormal Mild transaminase elevation (less than three times normal): monitoring every 1 to 2 weeks: if stable and patient is responding to valproate, results are monitored monthly to every 3 months Pronounced transaminase elevation (more than three times normal): dosage reduction or discontinuation of valproate; increase dose or rechallenge if transaminases normalize and if the patient is a valproate responder

23. For treatment of acute mania, an oral loading strategy of initiation with 20 to 30 mg/kg a day can be used to accelerate control of symptoms.

24. Carbamazepine  Carbamazepine is absorbed slowly.  Bioavailability is 80 percent  Peak plasma levels are reached 2 to 8 hours after a single dose.  Carbamazepine is 70 to 80 percent bound to plasma protein.  The average half-life after a single dose is 26 hours, with a range of 18 to 54 hours.  autoinduction

25. Therapeutic Indications Bipolar Disorder Acute Mania Prophylaxis Other Disorders

26. Dosage-Related Adverse Effects Double or blurred vision Vertigo Gastrointestinal (GI) disturbances Task performance impairment Hematologic effects Idiosyncratic Adverse Effects Hepatic failure Agranulocytosis Aplastic anemia Rash Stevens-Johnson syndrome Pancreatitis

27. Carbamazepine occasionally activates vasopressin receptor function (SIADH), characterized by hyponatremia and, rarely, water intoxication. Emergence of confusion, severe weakness, or headache in a person taking carbamazepine should prompt measurement of serum electrolytes.

28. Routine Laboratory Monitoring  Complete laboratory blood assessments may be performed every 2 weeks for the first 2 months of treatment and quarterly thereafter.  Carbamazepine treatment should be discontinued: WBC below 3,000/mm 3, erythrocytes below 4.0 أ — 10 6 /mm 3, neutrophils below 1,500/mm 3, hematocrit less than 32 percent, hemoglobin less than 11 g/100 mL, platelet count below 100,000/mm 3 reticulocyte count below 0.3 percent serum iron concentration below 150 mg/100 mL

29. Lamotrigine Lamotrigine (Lamictal) was originally developed as an antiepileptic drug used as adjunctive therapy for general and partial seizures in adults and pediatric patients. It was approved by the US Food and Drug Administration (FDA) for maintenance treatment of bipolar I disorder in 2003. In clinical trials, it was shown to keep patients euthymic longer and was particularly effective in preventing depressive episodes.

30. Therapeutic Indications Bipolar Disorder Lamotrigine is indicated in the maintenance treatment of bipolar disorder and may prolong the time between episodes of depression and mania. It is more effective in lengthening the intervals between depressive episodes than manic episodes. It is also effective as treatment for rapid-cycling bipolar disorder. Other Indications

31. Precautions and Adverse Reactions The most common adverse effects—dizziness, ataxia, somnolence, headache, diplopia, blurred vision, and nausea are typically mild. Cognitive impairment and joint or back pain may occur. Rash: Benign maculopapular rash :8% Stevens-Johnson syndrome or toxic epidermal necrolysis 0.08%- 0.13%

32. Drug Interactions The most potentially serious lamotrigine drug interaction involves concurrent use of valproic acid, which doubles serum lamotrigine concentrations conversely.

33. Lamotrigine Lamotrigine Topiramate Topiramate Gabapentin Gabapentin Antipsychotics Antipsychotics Classic (Haloperidol) Classic (Haloperidol) Novel (Clozapine, Olanzapine) Novel (Clozapine, Olanzapine)