Antidepressants and Treatment of Mood Disorders

1. Antidepressants and Treatment of Mood Disorders Anita S. Kablinger M.D. Associate Professor Departments of Psychiatry and Pharmacology

2. Outline of Lecture • Definitions • DSM-IV diagnoses and criteria • Epidemiology • Neurobiology • Psychosocial theories • Treatments

3. Definitions • Depression can refer to many things and mean different things to different people • Symptom versus syndrome • However, for a clinical depression consistent with DSM-IV, this must lead to functional impairment

4. Major Depression Dysthymia Depressive Disorder NOS Bipolar Disorder, Type I or II Cyclothymia Bipolar Disorder NOS Mood Disorder secondary to GMC Substance-Induced Mood Disorder Adjustment Disorder (separate classification) DSM-IV Diagnostic Categories

5. Epidemiology • Depression is the most common cause of disability in the world • U.S. costs approximate 43$ billion per year for mood disorders • Lifetime prevalence rates: (according to NCS), 21-24% for women and 12-15% for men

6. >2 week period of change in behavior with 5 of the following: *depressed mood *anhedonia appetite disturbance sleep disturbance psychomotor disturbance fatigue or loss of energy worthlessness or guilt impaired concentration suicidal thoughts * 1/5 symptoms must be these Rule out physical cause Major Depressive Disorder (MDD)

7. Time Course of MDD • Often lasts for a year without treatment • Chances increase by 50% for another episode after current episode (i.e. high relapse and recurrence rates) • Many go on to experience chronic depression (but may be a result of inadequate treatment)

8. Heritability of Mood Disorders • Genetic factors very important • RR of MDD is 2-5x greater in relatives of depressed patients than controls • First degree relatives of Bipolar patients are 24x more likely to develop BAD than general population • Twin and adoption studies help to understand and define this illness

9. Psychosocial Theories of Depression • Risk factors include: • recent stressors • poor social support system • history of early parental loss • gender • family history of depression • negative cognitive style

10. Theories of Depression • NE and DA broken down to variety of products through MAO and COMT • 5HT is broken down by MAO to 5-HIAA • Major mechanism for terminating signal is neuronal reuptake • Monoaminergic Theories • Reserpine (early antihypertensive) • Iproniazid (used to treat TB) • Imipramine (originally studied as an antipsychotic) • Drugs enhancing noradrenergic functioning were antidepressants (eg. stimulants)

11. Indoleamine Hypothesis of Depression • Serotonin is functionally deficient in depression • Decreased brain 5-HT and CSF 5-HIAA in many depressed patients • Antidepressants tend to increase central serotonin transmission • Depressed patients show reduction in 5-HT reuptake sites • Blunted neuroendocrine challenges

12. Neurotransmitter Hypothesis of Mood Disorders • Led to catecholamine hypothesis • NE ↓ in depression and  in mania • 5-HT ↓ production or reuptake in depression • Flaws: depression or mania not reliably produced and clinical response exceeds mechanism of action of drug

13. Neurobiology of Mood Disorders • Neuroendocrine abnormalities: reflect central neurotransmitter dysfunction • hyperactivity of HPA: increased cortisol, nonsuppression of cortisol in DST • blunting of TSH release following TRH infusion • blunting of GH release with alpha-2 adrenergic agonism and serotonin-mediated increases in prolactin

14. Other Alterations in Depression •  CRH •  acetylcholine activity •  GABA levels • Excessive glucocorticoid activity in psychotic depression • Hippocampal volume loss

15. Neurobiology of Mood Disorders • Sleep abnormalities: usually found in endogenous depression • prolonged sleep latency • shortened REM latency and change in timing • increased wakefulness • decreased arousal threshold • early morning awakening • reduced stage 3 and 4 sleep

16. Kindling-Sensitization Hypothesis of Mood Disorders • Suggests that repeated exposure to stress and/or neurochemical changes during depressed episode sensitize brain regions responsible for affect • Repeated episodes may permanently alter systems within the CNS • Leads to shorter well periods, increased frequency and severity of illness

17. Treatments • Pharmacotherapy • Psychotherapy • Social interventions • ECT • TMS • VNS

18. Which Medication? • Safety • Tolerability • Efficacy • Payment • Simplicity

19. Available Types of Pharmacotherapy • Tricyclic antidepressants (TCA) • MAOI’s • SSRI’s • SNRI’s • Atypical antidepressants • Mood stabilizers • Antipsychotics

20. General Treatment Rules • Often takes 4-6 weeks for response • Monitor for response versus remission • Vegetative symptoms tend to improve first, cognitive symptoms take longer • SSRI’s are the first line of treatment for most MDD’s • Address biopsychosocial needs and maintain meds for 6-12 months

21. Tricyclic Antidepressants • Available for more than 30 years • Cheap but not clean • Act by NE and/or 5 HT presynaptic reuptake inhibition • Side effects include anticholinergic effects, orthostasis, slowing of cardiac conduction • Secondary better than tertiary compounds

22. Selective Serotonin Reuptake Inhibitors • Produce response rates close to 70% • Safer and better tolerated than TCA’s • Given once daily • Starting and therapeutic doses often similar • Most common side effects include GI symptoms, HA, insomnia, anxiety, and sexual dysfunction • Five available in the U.S.

23. Novel or Atypical Antidepressants • Bupropion (NE and DA reuptake inhibition) • Trazodone (5 HT2 alpha-ANT) • Venlafaxine and Duloxetine (NE and 5 HT reuptake blockers – SNRI’s) • Mirtazapine (presynaptic alpha 2 ANT and 5 HT2 and 5 HT3 ANT)

24. Psychotherapy in Depression • Supportive • Insight-oriented • Interpersonal • Cognitive-behavioral • Psychodynamic • Individual, group or family