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. DSM-IV Diagnostic Categories 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)

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. Major Depressive Disorder (MDD) >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

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