1. Drugs for Bipolar Disorders Kaukab Azim, MBBS, PhD

2. Drug List For Treatment of Acute ManiaFor Maintenance Treatment First Line DrugsSecond Line DrugsFirst Line DrugsSecond Line Drugs LithiumCarbamazepine*LithiumCarbamazepine* Valproate*Lamotrigine*Valproate* Olanzapine*Lamotrigine* Quietapine*Olanzapine* Risperidone* Aripiprazole* Haloperidol* Clozapine* * These drugs have been mentioned in other lectures

3. Learning Outcomes By the end of the course the students should be able to  Explain the mechanism of action of drugs used in acute mania  Explain the mechanism of action of lithium  Describe the main pharmacokinetics of lithium  Describe the adverse effects of lithium.  Outline the main drug interactions of lithium.  Outline the main contraindications of lithium  Describe the main therapeutic uses of lithium.  Outline the therapeutic uses of valproate, an carbamazepine in bipolar disorder.  Outline the use of neuroleptics in bipolar disorder.

4. Classification of Bipolar Disorders* TypeFeatures Bipolar disorder type 1 A manic episode ± major depressive or mixed episode Bipolar disorder type 2 A major depressive episode ± hypomanic episode Cyclothymic disorder Chronic fluctuation between subsyndromal and hyomanic episodes (at least 2 years for adults) Bipolar disorder not other wise specified Any bipolar disorder that does not meet criteria for any specific bipolar disorder * From DSM iV text revision

5. Theories of Bipolar Disorder Genetic factors 80-90% of patients with bipolar disorder have a biologic relative with a mood disorder. The concordance rate of mood disorders is 60-80% for monozygotic twins and 14-20% for dizygotic twins. Non-genetic factors Stressful life events often precede mood episodes and can increase recurrence rate of them. Changes in sleep -wake cycle can precipitate episodes of mania. Bright light therapy, used in the treatment of winter depression can precipitate ipomania.

6. Neurotransmitter/neuroendocrine theories Monoamine hypothesis An excess of catecholamines (primarily NE an DA) can cause mania. Deficit of monoamines (primarily NE, DA and/or 5- HT) can cause depression. Cholinergic hypothesis Drug that increase cholinergic activity can decrease manic symptoms Dysregulation of amino acid neurotransmitters Drugs that increase GABA activity or decrease glutamate activity are used for treatment of mania (lithium, lamotigrine, valproic acid)

7. Theories for Bipolar Disorder Dysregulation of secondary messenger system Abnormal adenyl cyclase activity, abnormal phosphoinositide responses, abnormal Na+, K+ and Ca++ channel exchanges. Dysregulation of hypothalamic, pituitary, thyroid axis. Hyperthyroidism can precipitate manic symptoms Hypothyroidism can trigger depression and is a risk factor for rapid cycling. Sensitization and kindling Recurrences of mood episodes causes electrophysiological kindling an can result in rapid or continuous mood cycling.

8. Lithium Drug Lithium is a small monovalent cation (MW: 6.9). Main mechanisms of action Li+ is classified as a mood-stabilizing drug because it can reduce both manic and depressive symptoms of bipolar disorder.

9. The precise mechanism of its therapeutic effect is unknown but is likely related to inhibition of two signal transduction pathways: 1) Inositol signaling Li+ inhibits inositol monophosphatase, the rate-limiting enzyme involved in inositol recycling. This leads to: – Depletion of phosphatidylinositol-4,5-bisphosphate ( PIP2) which is the precursor of IP3 and DAG – Inhibition of the synthesis of IP3 and DAG – Inhibition of the activity of many receptors that are IP3/DAG linked. This is the major current working hypothesis for lithium therapeutic mechanism of action

10. Lithium 2) Glycogen synthase kinase-3 signaling – Li+ inhibits glycogen synthase kinase-3, a protein-kinase that regulate signal pathways involved in apoptosis. – suppression of the expression of pro-apoptotic genes and increase expression of anti-apoptotic genes. – The ultimate effect is neuro-protection which could underlie long term mood stabilization (increased neurogenesis has been found in the hippocampus after lithium treatment)

11. Additional mechanisms of action 1)Actions on other second messenger systems Li+ inhibits norepinephrine-sensitive adenyl cyclase, which results in a decrease of cAMP. Li+ enhances GABAergic activity and reduces glutamatergic activity 2.Actions on electrolytes and ion transport Li+ can mimic the role of Na+ in excitable tissues. It goes across cell membranes an Na+ sodium in action potential. It is not pumped out by Na+/K+ ATPase and therefore it tends to accumulate inside the cells, displacing Na+. Ca++/Na+ exchanger is not significantly affected at therapeutic concentration

12. Effect of lithium on the IP 3 (inositol trisphosphate) and DAG (diacylglycerol) second- messenger system. The schematic diagram shows the synaptic membrane of a neuron. (PIP 2, phosphatidylinositol-4,5-bisphosphate; PLC, phospholipase-C; G, coupling protein; Effects, activation of protein kinase C, mobilization of intracellular Ca 2+, etc.) Lithium, by inhibiting the recycling of inositol substrates, may cause depletion of the second- messenger source PIP 2 and therefore reduce the release of IP 3 and DAG. Lithium may also act by other mechanisms. (Katzung 2011) Lithium

13. Pharmacological effects CNS effects At therapeutic doses Li+ has no mental effects on normal individual. The calming effect in manic patients develops slowly (several day or weeks). Cardiovascular effects Depression of the SA node T wave depression or inversion (likely due to intracellular myocardial K+ depletion by displacement with Li+). Renal effects Inhibition of vasopressin action on the kidney (likely due to inhibition of adenyl cyclase) Lithium

14. Endocrine and metabolic effects Inhibition of thyroid hormone synthesis (TSH-induced production of cAMP in thyroid cells is inhibited, due to inhibition of adenylyl cyclase) ECF expansion (during the first days of therapy. Li+ tends to accumulate inside the cells, displacing Na+). Pharmacokinetics Oral bioavailability: 100% Distribution in total body water (Vd. 45 L) No metabolism Excretion: 97% in the urine (80% is reabsorbed in the proximal tubule, some is reabsorbed in the collecting duct). Half -life: 20 hours (Accumulation can be a problem due to the long half life) Lithium

15. CNS Fine hand tremor (up to 50%. Beta-blockers can be useful) Memory impairment, mental confusion, poor concentration (up to 40%) Muscle weakness, lethargy (up tp 30%) Motor hyperactivity, ataxia, aphasia, seizures (with high doses). Metabolic/Endocrine system Hypothyroidism (5-8%) Weight gain (up to 30%) Lithium Adverse effects

16. Urinary system Polyuria, polydipsia (up to 70%) Nephrogenic diabetes insipidus (12% after long term treatment). Gastrointestinal system Nausea, epigastric bloating, diarrhea (6-20%). Adverse effects Cardiovascular system Edema, frequent during the first 5-7 days of therapy (likely due to increased NA+ in the ECF). Hypotension, arrhythmias sinus bradycardia, SA / AV block Other systems Leukocytosis (very frequent) Acneiform skin eruptions

17. Overdosage Li+ has a narrow therapeutic index (about 2-3) and Li+ plasma levels must always be monitored. Symptoms of overdosage include lethargy, apathy, unsteady gait, mental confusion, muscle twitches, seizures, stupor, coma and cardiovascular collapse. Pregnancy Disagreement exists about the importance of teratogenic effects of Li+ However the drug is rated pregnancy category D by FDA Ebstein’s anomaly of the tricuspid valve is the main teratogenic effect.

18. Drug interactions of Clinical Importance DrugType of Interaction Thiazides, Loop diuretics Increased Li + plasma levels (increased Na + elimination enhances Li + reabsorption in the proximal tubules) NSAIDs Increased Li + plasma levels (reduced renal prostaglandin production decreases renal elimination of Li + ) ACE inhibitors, angiotensin blockers (ARBs) Increased Li + plasma levels (mechanism is unknown) SSRIs Serotonin syndrome may occur (mechanism is unknown) Carbamazepine Increased neurotoxicity of Li+ (ataxia, tremor, hyperreflexia. Mechanism is unknown Iodide salts Risk of Li+ induced hypothyroidism is increased

19. Main uses  Manic phase of bipolar disorders (often with concurrent use of antipsychotics or benzodiazepines during the first few days)  Maintenance treatment of bipolar disorder (maintenance treatment can prevents or diminishes the intensity of subsequent episodes of both mania and depression. Treatment must be continued for at least 6-9 months; in severe cases even for life).  Schizoaffective disorder (together with antipsychotic drugs).  Depressive disorder (augmenting agent for antidepressants). Lithium Therapeutic uses

20. Unlabeled/Investigational uses  Aggression, post-traumatic stress disorder, conduct disorder in children

21. Anticonvulsants for Bipolar Disorder Drugs Valproate, lamotigrine and carbamazepine are the main anticonvulsant drugs with mood stabilizing properties. Mechanism of action Still uncertain. Actions similar to those of Li +, which seems to mediate the mood stabilizing properties include: a.Inhibition of adenylyl cyclase b.Reduction of inositol generation in the inositol signaling pathway c.Activation of neuroprotective genes

22. Pharmacological and adverse effects (these are discussed under antiseizure drugs) Therapeutic uses in bipolar disorders As monotherapy in acute mania or mixed states As monotherapy in acute bipolar depression As maintenance therapy

23. Atypical Neuroleptics for Bipolar Disorder Drugs Aripiprazole, olanzapine, quetiapine, risperidone. Mechanism of action, pharmacological and adverse effects (these are discussed under neuroleptic drugs) Therapeutic uses in bipolar disorders As monotherapy or adjunctive therapy in acute mania or mixed states As adjunctive therapy in acute bipolar depression (risperidone, olanzapine)

24. Therapy for Bipolar Disorder DisorderFirst Line DrugsSecond Line Drugs Acute Mania or mixed states Lithium Valproate Carbamazepine Aripiprazole Olanzapine Quetiapine Risperidone Lamotrigine (for rapid cycling) Acute bipolar depression Lithium Lamotrigine Carbamazepine Valproate Maintenance therapy Lithium Valproate Lamotrigine Olanzapine Carbamazepine

25. Therapy for Bipolar Disorder Hypomania Lithium or valproate or carbamazepine (if response is inadequate) Lithium plus an anticonvulsant or an atypical neuroleptic Mania Lithium or valproate plus lorazepam (if response is inadequate) Lithium plus an anticonvulsant plus an atypical neuroleptic Mild bipolar depression Lithium or lamotrigine Severe bipolar depression Lithium plus an SSRI (if response is inadequate) Lithium plus lamotrigine plus an SSRI