Drugs for Bipolar Disorders

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

2. Drug List

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*

5. Theories of Bipolar Disorder Genetic factors • 80-90% of patients with bipolar disorder have a biologic relative with a mooddisorder. • The concordance rate of mood disorders is 60-80% for monozygotic twins and 14-20% for dizygotictwins. 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 Dysregulationof 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) Inositolsignaling • 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 • Actions on other second messenger systems • Li+ inhibits norepinephrine-sensitive adenylcyclase, which results in a decrease of cAMP. • Li+ enhances GABAergic activity and reduces glutamatergic activity • 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. Lithium Effect of lithium on the IP3 (inositol trisphosphate) and DAG (diacylglycerol) second-messenger system. The schematic diagram shows the synaptic membrane of a neuron. (PIP2, phosphatidylinositol-4,5-bisphosphate; PLC, phospholipase-C; G, coupling protein; Effects, activation of protein kinase C, mobilization of intracellular Ca2+, etc.) Lithium, by inhibiting the recycling of inositol substrates, may cause depletion of the second-messenger source PIP2 and therefore reduce the release of IP3 and DAG. Lithium may also act by other mechanisms. (Katzung 2011)

13. Lithium 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 adenylcyclase)

14. Lithium Endocrine and metabolic effects • Inhibition of thyroid hormone synthesis (TSH-induced production of cAMPin 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)

15. Lithium Adverse effects 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/Endocrinesystem • Hypothyroidism (5-8%) • Weight gain (up to 30%)

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 Dby FDA • Ebstein’s anomaly of the tricuspid valve is the main teratogenic effect.

19. Lithium Therapeutic uses 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).

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: • Inhibition of adenylyl cyclase • Reduction of inositol generation in the inositol signaling pathway • Activation of neuroprotectivegenes

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

25. Therapy for Bipolar Disorder