Pharmacology of Antidepressants and Mood Stabilizers

1. Pharmacology of Antidepressants and Mood Stabilizers Philip G. Janicak, M.D. Professor of Psychiatry and Pharmacology University of Illinois at Chicago

2. pharmacology of antidepressants and mood stabilizers Objectives • Review the signs and symptoms of major depression and bipolar disorder • Characterize the different classes of antidepressants and mood stabilizers based on their mechanism of action • Review the pharmacokinetics, adverse effects and potential for drug interactions of these agents • Review treatment strategies for the drug management of depression and bipolar mania based on the existing data, clinical experience, and risk-benefit ratio

3. pharmacology of antidepressants and mood stabilizers Depression: Diagnosis • Clinical depression is common, but often misdiagnosed • About 50% of suicides are associated with depression • Depression can adversely impact other medical conditions • Comorbid anxiety is frequent and can substantially increase suicide risk • Although ³70% of depressions can respond to appropriate medication, many patients never receive an adequate trial

4. pharmacology of antidepressants and mood stabilizers Diagnostic Indications forAntidepressants (DSM-IV Categories) Mood disorders Major depressive disorder Single of recurrent With or without melancholia Seasonal pattern Bipolar disorder Depressed Mixed Cyclothymic disorder Dysthymic disorder Other psychotic disorders (e.g., schizoaffective disorder, depressive type) Mood disorder due to a general medical condition e.g., dementia with depression (e.g., Alzheimer’s type, vascular) Substance-induced mood disorder e.g., amphetamine or similarly acting synpathomimetic intoxication or withdrawal

5. pharmacology of antidepressants and mood stabilizers DSM-IV Diagnostic Criteria for aMajor Depressive Episode Presence of at least five of the following symptoms during the same 2-week period (nearly every day), representing a change from previous functioning; at least one symptom is either (a) depressed mood, or (b) loss of interest or pleasure. Mood • Depressed mood (irritable mood in children and adolescents) • Marked diminished interest or pleasure in almost all activities Behavioral • Significant weight loss or gain (failure to attain expected weight gain in children) • Insomnia or hypersomnia • Observable psychomotor agitation or retardation • Fatigue or loss of energy Cognitive • Feelings of worthlessness, or of excessive or inappropriate guilt • Diminished ability to think or concentrate, or indecisiveness • Recurrent thoughts of death; recurrent suicidal ideation, plans, or attempts

6. Pharmacotherapy Antidepressants Anxiolytics Mood stabilizers Antipsychotics Psychotherapy Cognitive behavioral therapy Interpersonal therapy Marital/family counseling Group therapy pharmacology of antidepressants and mood stabilizers THERAPEUTIC OPTIONS Somatic Therapy • Electroconvulsive therapy • Bright light therapy • Possibly: • Transcranial magnetic stimulation • Vagal nerve stimulation • Sleep deprivation

7. pharmacology of antidepressants and mood stabilizers Major Classes of Antidepressants Defined by Putative Mechanism of Action • Combined NE and SE uptake inhibition • Tricyclic antidepressants (TCAs) • Venlafaxine • SE uptake inhibition • Serotonin selective reuptake inhibitors (SSRIs) • 5-HT2 receptor blockers and SE uptake inhibition • Nefazodone (phenylpiperazine) • DA and NE uptake inhibition • Bupropion (aminoketone) • Monoamine oxidase inhibitors (MAOIs) • Nonselective and irreversible • Selective and/or reversible (RIMAs) Preskorn SH. Outpatient Management of Depression. 1994.

8. pharmacology of antidepressants and mood stabilizers Pharmacodynamics of Antidepressants • Norepinephrine receptors • Postsynaptic (alpha1 and alpha2; beta1and beta2) • Presynaptic (alpha2) • Serotonin receptors • Postsynaptic (5-HT1A and 5-HT2) • Presynaptic (5-HT1A) • Others • Dopamine • Acetylcholine

9. pharmacology of antidepressants and mood stabilizers

10. pharmacology of antidepressants and mood stabilizers Components of a Synapse

11. pharmacology of antidepressants and mood stabilizers Cascade of Intraneuronal Events

12. pharmacology of antidepressants and mood stabilizers Psychopharmacology of Mirtazapine

13. pharmacology of antidepressants and mood stabilizers Monoamine Oxidase Inhibitors • Nonselective/nonreversible • Hydrazine (e.g., phenelzine) • Nonhydrazine (e.g., tranylcypromine) • Selective/nonreversible • MAO-B (e.g., deprenyl) • Selective/reversible • MAO-A (e.g., moclobemide)

14. pharmacology of antidepressants and mood stabilizers Antidepressants:Adverse Effects, Pharmacokineticsand Drug-Interactions

15. pharmacology of antidepressants and mood stabilizers Potential Side Effects of Antidepressant Therapy Central Nervous System Dizziness, cognitive impairment, sedation, light-headedness, somnolence, nervousness, insomnia, headache, tremor,changes in satiety and appetite Cardiac Orthostasis, hypertension, heart block,tachycardia Gastrointestinal Nausea, constipation, vomiting, dyspepsia, diarrhea Urogenital Erectile dysfunction, ejaculation disorder, anorgasmia, priapism Autonomic Nervous System Dry mouth, urinary retention, blurred vision, sweating

16. pharmacology of antidepressants and mood stabilizers DRUG Chlorpheniramine Bentropine Desipramine SSRI Nefazodone Cimetidine Prazosin Yohimbine Quinidine ACTION H1 receptor blockade Acetylcholine receptor blockade NE reuptake inhibitiona 5-HT reuptake inhibitiona 5-HT2 receptor blockade H2 receptor blockade 1 receptor blockade Alpha2 NE receptor blockade Direct membrane stabilization Polypharmacy with a Single Drug: “Cocktail” of Effects of the Tricyclic Antidepressant Amitriptyline © Preskorn S: Outpatient Management of Depression, Professional Communications, Inc. Caddo, Oklahoma, 1994. a Venlafaxine combines these two actions over its clinically relevant dosing range.

17. pharmacology of antidepressants and mood stabilizers Selective Serotonin Reuptake Inhibitors • Improved safety and tolerability (e.g., cardiac toxicity) • Better compliance long-term • Multiple therapeutic effects, including: • Antipanic • Antiobsessional • Other disorders (e.g., PTSD; PMDD)

18. pharmacology of antidepressants and mood stabilizers Comparison of Pharmacokinetic Parameters Citalopram Fluoxetine Sertraline Paroxetine Fluvoxamine % protein bound 80 94 99 95 77 Peak plasma level (hour) 3-4 6-8 6-8 2-8 2-8 Half-life (hours) 35 24-72 25 20 15 Dose range (mg/d) 20-60 20-80 50-200 10-50 50-300 Absorption altered by fast or fed status No No Yes No No Linear pharmacokinetics Yes No Yes No No GI absorption (%) ~100 80 44 64 94 Van Harten. Clin Pharmacokinet, 1993. Preskorn. Clin Pharmacokinet, 1997. Data on file, Forest Laboratories, Inc. Preskorn. J Clin Psychiatry, 1993.

19. pharmacology of antidepressants and mood stabilizers Drug-Drug Interactions • The pharmacologic action of a drug may be altered by the coadministration of a second drug by: • increasing or decreasing a known effect • creating an adverse effect • creating in a new effect not seen with either drug alone • Interaction may be pharmacodynamic, pharmacokinetic, or idiosyncratic

20. pharmacology of antidepressants and mood stabilizers Antidepressants andthe Cytochrome P450 System • Antidepressants and mood stabilizers may be inhibitors, inducers, or substrates of one or more cytochrome P450 isoenzymes • Knowledge of their P450 profile is useful in predicting drug-drug interactions • When some isoenzymes are absent or inhibited, others may offer a secondary metabolic pathway • P450 1A2, 2C (subfamily), 2D6, and 3A4 are especially important to antidepressant metabolism and drug-drug interactions

21. pharmacology of antidepressants and mood stabilizers Minimizing the Risk of Drug-drug Interactions Associated With Antidepressants • When adding an antidepressant with a potential for pharmacokinetic interaction to another drug, clinicians could: • Reduce the dose of the current drug • Begin with a low dose of the antidepressant • Use therapeutic drug monitoring, where appropriate • Monitor therapeutic and adverse effects • Choose an antidepressant with a favorable profile for that interaction

22. Major depressive episode mild to moderate single or recurrent nonpsychotic SSRI, VENLAFAXINE, NEFAZODONE, OR MIRTAZAPINE (if expense not an issue) (or) USE PREVIOUSLY EFFECTIVE AD (at least 6 weeks with adequate dose and/or plasma level) (or) HCA (if side effects are tolerated; preferably a secondary amine TCA) Treatment of an AcuteMajor Depressive Episode CLINICAL PRESENTATIONTREATMENT STRATEGY start

23. Bipolar, depressed SWITCH CLASS of AD (e.g., HCA SSRI) (or) AD plus MOOD STABILIZER (possibly lamotrigine) Treatment of an AcuteMajor Depressive Episode CLINICAL PRESENTATIONTREATMENT STRATEGY start (insufficient response)

24. Atypical depression MONOAMINE OXIDASE INHIBITOR (MAOI) (N.B.: Must wait at least 5 weeks after fluoxetine; 2-3 weeks after other SSRIs, venlafaxine, nefazodone, mirtazapine) Treatment of an AcuteMajor Depressive Episode CLINICAL PRESENTATIONTREATMENT STRATEGY start (insufficient response)

25. COMBINE with LITHIUM (or) THYROID SUPPLEMENT (or) BUSPIRONE (or) PSYCHOSTIMULANT (or) PINDOLOL Treatment of an AcuteMajor Depressive Episode CLINICAL PRESENTATIONTREATMENT STRATEGY partial response (insufficient response)

26. TWO DIFFERENT ADs CONCURRENTLY (e.g., add MAOI or SSRI slowly to TCA; NB: Do not use an MAOI plus SSRI, venlafaxine, nefazodone, mirtazapine?) Treatment of an AcuteMajor Depressive Episode CLINICAL PRESENTATIONTREATMENT STRATEGY (if psychosis emerges)

27. ANTIPSYCHOTIC plus AD Treatment of an AcuteMajor Depressive Episode CLINICAL PRESENTATIONTREATMENT STRATEGY • Psychotic depression start (insufficient response) or • Serious suicidal risk • Rapid physical deterioration • Prior history of nonresponse to medication and /or good response to ECT may start ELECTROCONVULSIVE THERAPY

28. pharmacology of antidepressants and mood stabilizers Bipolar Disorder: Major Points • Bipolar and related disorders are some of the most challenging conditions to diagnose and manage • Pharmacotherapy is the primary treatment • Lithium is often insufficient • Anticonvulsants and second generation antipsychotics may be effective alternatives or supplements

29. pharmacology of antidepressants and mood stabilizers Bipolar Disorder: General Considerations • Afflicts about 1% of the population • Psychosocial/environmental stressors influence occurrence • Birth cohort effect/genetic risk • About 25-30% will develop some symptoms before age 20 • 35-60% of bipolar patients abuse alcohol and/or other drugs

30. pharmacology of antidepressants and mood stabilizers Bipolar Disorder: Long-Term Prognosis • High morbidity and mortality • Overall, 11% suicide rate • Untreated, 20-25% will commit suicide • Suicide rate is highest during depressive or mixed phase of illness Goodwin and Jamison, 1990

31. Mania Euphoria Grandiosity Pressured speech Impulsivity Excessive libido Recklessness Diminished need for sleep Depression Depression Anxiety Irritability Hostility Violence or suicide pharmacology of antidepressants and mood stabilizers Bipolar Disorder: Symptom Domains Manic, depressed or mixed Episode • Cognition • Racing thoughts • Distractability • Poor insight • Disorganization • Inattentiveness • Confusion • Psychosis • Delusions • Hallucinations • Sensory hyperactivity

32. pharmacology of antidepressants and mood stabilizers Treatment of Bipolar Disorder Mood stabilizers* Lithium Valproate Olanzapine * FDA approved Anticonvulsants Carbamazepine Lamotrigine Topiramate Gabapentin Second generation antipsychotics Clozapine Risperidone Quetiapine Ziprasidone Aripiprazole Iloperidone Nonpharmacologic therapies CBT Other psychotherapies Somatic therapies ECT Light therapy TMS; VNS (?)

33. pharmacology of antidepressants and mood stabilizers 40 years of clinical experience Effective for euphoric mania and hypomania Reduces mortality rate, primarily by decreasing suicide FDA labeled indication Inexpensive Narrow therapeutic index Slow onset of action Numerous adverse effects High noncompliance rate Less effective for certain subtypes Lithium ADVANTAGES DISADVANTAGES

34. pharmacology of antidepressants and mood stabilizers Lithium Neurotransmitters NE () NE/AcH Balance Hypothesis DA  () 5HT () Permissive Hypothesis GABA  () GLU ACH () Signal Transduction G-Protein -PLC  AC (cAMP) () 2nd Messenger Dysbalance Hypothesis Ionositol (IMP) () Inositol-Depletion Hypothesis cGMP  () PKC (,) -MARKS  () GSK-3 AP-1 (fos,jun)  () -DNA BINDING

35. pharmacology of antidepressants and mood stabilizers Lithium Ion Channels Ca++ Na++ Cl- K+ Other Thyroid () Thyroid-Catecholamine Hypothesis Circadian Rhythms  Neurotropic/ Neuroprotective  (?)

36. pharmacology of antidepressants and mood stabilizers Anticonvulsants • Valproate • Carbamazepine • Lamotrigine • Gabapentin • Topiramate • Tiagabine • Others

37. Rapid onset Can be used as initial treatment High quality of clinical studies Effective in bipolar subtypes FDA labeled indication Limited long-term data Side effects weight gain tremors pancreatitis hepatotoxicity pharmacology of antidepressants and mood stabilizers Valproate ADVANTAGES DISADVANTAGES

38. pharmacology of antidepressants and mood stabilizers Anticonvulsants Neurotransmitters VPA CBZ LTG GBN TOP NE  () DA  ()  () 5HT  () GABA ()  ()  GLU  ()  (?)  Signal Transduction AC  () IMP  () cGMP  () PKC () AP-I  ()

39. pharmacology of antidepressants and mood stabilizers Anticonvulsants VPA CBZ LTG GBN TOP Ca++ () Na++ ()  Cl- K+  Thyroid () CAI  ION Channels Other

40. pharmacology of antidepressants and mood stabilizers Second Generation Antipsychotics • Olanzapine • Clozapine • Risperidone • Quetiapine • Ziprasidone

41. Quality of trials for bipolar mania Benefits both mood and psychotic symptoms Possibly more rapid onset of action FDA-labeled indication Limited long-term data Side effects Weight gain Diabetes / DKA (?) EPS pharmacology of antidepressants and mood stabilizers Olanzapine ADVANTAGES DISADVANTAGES

42. pharmacology of antidepressants and mood stabilizers Second Generation Antipsychotics CLZ RISP OLZ QTP ZPD NE 5-HT  DA  AcH  Neurotransmitters

43. pharmacology of antidepressants and mood stabilizers Mood Stabilizers:Adverse Effects, Pharmacokineticsand Drug-Interactions

44. pharmacology of antidepressants and mood stabilizers Lithium: Adverse Effects

45. pharmacology of antidepressants and mood stabilizers Anticonvulsants: Adverse Effects

46. pharmacology of antidepressants and mood stabilizers Pharmacokinetic Propertiesof Primary Mood Stabilizers

47. pharmacology of antidepressants and mood stabilizers Drug Interactions with Mood Stabilizers • Lithium • Renal excretion • Anticonvulsants (e.g., carbamazepine) • Enzyme induction • Second generation antipsychotics

48. Mild to Moderate Symptoms LITHIUM (0.8 - 1.2mEq/L) or VPA (50-125 ug/mL)* Strategy for Treatment of Acute Mania CLINICAL PRESENTATIONTREATMENT STRATEGY start (insufficient response; marked agitation) *Consider loading dose strategy (i.e., 20 to 30 mg/kg/day)

49. add BENZODIAZEPINE as adjunct (e.g., lorazapam 1-2mg i.m.) Strategy for Treatment of Acute Mania CLINICAL PRESENTATION TREATMENT STRATEGY (insufficient response)

50. WITHDRAW ANTIDEPRESSANT if present THYROID SUPPLEMENT if TSH elevated Strategy for Treatment of Acute Mania CLINICAL PRESENTATIONTREATMENT STRATEGY (insufficient response)