1. Diagnosis and Psychopharmacological Treatment of Major Depressive Disorder Dr. James K. Rustad, M.D. Copyright © 2011. All Rights Reserved.

2. Presentation Overview Definitions of Major Depressive Episode and Major Depressive Disorder Suicide risk assessment: SAD PERSONS Pathophysiology and Neurobiology of Depression

3. Psychopharmacological Treatment of MDD Monoamine Oxidase Inhibitors (MAOIs ) Tricyclic Antidepressants (TCAs) Selective serotonin reuptake inhibitors (SSRIs) Serotonin norepinephrine reuptake inhibitors (SNRIs) Norepinephrine dopamine reuptake inhibitor (NDRI) Bupropion) Alpha-two antagonist (Mirtazapine) Serotonin antagonist/reuptake inhibitor (SARI: Trazodone) Combination and Augmentation Strategies for Treatment- Resistant Depression

4. Major Depressive Episode from DSM-IV TR (4 th edition), 2000. A. Five (or more) of the following symptoms have been present during the same 2-week period and represent a change from previous functioning; at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure. Note: Do note include symptoms that are clearly due to a general medical condition, or mood-incongruent delusions or hallucinations. (1) depressed mood most of the day, nearly every day, as indicated by either subjective report (e.g., feels sad or empty) or observation made by others (e.g., appears tearful). Note: In children and adolescents, can be irritable mood. (2) markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day (as indicated by either subjective account or observation made by others) (3) significant weight loss when not dieting or weight gain (e.g., a change of more than 5% of body weight in a month), or decrease or increase in appetite nearly every day. Note: In children, consider failure to make expected weight gains. (4) insomnia or hypersomnia nearly every day

5. Major Depressive Episode from DSM-IV TR (4 th edition), 2000. (5) psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of restlessness or being slowed down) (6) fatigue or loss of energy nearly every day (7) feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly every day (not merely self-reproach or guilt about being sick) (8) diminished ability to think or concentrate, or indecisiveness, nearly every day (either by subjective account or as observed by others) (9) recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide

6. Major Depressive Episode from DSM-IV TR (4 th edition), 2000. B. The symptoms do not meet criteria for a Mixed Episode. C. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. D. The symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition (e.g., hypothyroidism). E. The symptoms are not better accounted for by Bereavement, i.e., after the loss of a loved one, the symptoms persist for longer than 2 months or are characterized by marked functional impairment, morbid preoccupation with worthlessness, suicidal ideation, psychotic symptoms, or psychomotor retardation.

7. Major Depressive Disorder, Single Episode from DSM-IV TR (4 th edition), 2000. A. Presence of a single Major Depressive Episode B. The Major Depressive Episode is not better accounted for by Schizoaffective Disorder and is not superimposed on Schizophrenia, Schizophreniform Disorder, Delusional Disorder, or Psychotic Disorder Not Otherwise Specified. C. There has never been a Manic Episode, a Mixed Episode, or a Hypomanic Episode. Note: This exclusion does not apply if all the manic-like, mixed-like, or hypomanic-like episodes are substance or treatment induced or are due to the direct physiological effects of a general medical condition.

8. Major Depressive Disorder, Recurrent from DSM-IV TR (4 th edition), 2000. A. Presence of two or more Major Depressive Episodes. Note: To be considered separate episodes, there must be an interval of at least 2 consecutive months in which criteria are not met for a Major Depressive Episode. B. The Major Depressive Episodes are not better accounted for by Schizoaffective Disorder and are not superimposed on Schizophrenia, Schizophreniform Disorder, Delusional Disorder, or Psychotic Disorder Not Otherwise Specified. C. There has never been a Manic Episode, a Mixed Episode, or a Hypomanic Episode. Note: This exclusion does not apply if all the manic-like, mixed-like, or hypomanic-like episodes are substance or treatment induced or are due to the direct physiological effects or a general medical condition.

9. Major Depressive Disorder, Recurrent from DSM-IV TR (4 th edition), 2000. Specify (for current or most recent episode): Severity/Psychotic/Remission Specifiers Chronic With Catatonic Features With Atypical Features With Melancholic Features With Postpartum Onset Specify Longitudinal Course Specifiers (With and Without Interepisode Recovery) With Seasonal Pattern

10. Phases of Depression: Recovery is the goal! Acute phase: 6-12 weeks Continuation phase: 4-9 months Maintenance phase: 1 or more years Stahl, Essential Psychopharmacology of Depression and Bipolar Disorder 2000.

11. Risk factors for Chronicity Prior history of multiple episodes: 50-85% of patients will have more than one episode and likelihood of additional episodes increases with each one Persistent Dysthymic Symptoms Comorbidity

12. Recurrence After first episode MDD, 50-60% chance of having second episode After second episode, 70% chance of having third After third episode, 90% chance of having fourth Recurrence more likely if patients not treated to Remission during given episode

13. Poor prognostic factors Psychotic/catatonic presentations Positive family history Death of near relative or partner/spouse Presence of disabled spouse Concurrent medical/psychiatric illness Substance abuse

14. Family history Depression is 1.5 to 3-fold times more common in patients with 1 st degree relative who suffers from the disorder In twin studies, monozygotic twins have two-fold greater concordance rates (50-70%) for MDD than dizygotic twins (20-25%)

15. Suicide Risk Asssesment Patterson et al., Psychosomatics 1983.

16. Proposed Model of Depression (from Mayberg, 1997) Limbic-Cortical Dysregulation Attentional and Cognitive Features of Illness: Dorsal Compartment (neocortical and midline limbic elements: DLPFC, dorsal anterior cingulate, inferior parietal cortex, striatum). Symptoms: Apathy, Psychomotor Slowing, Impaired selective/directed attention and executive function. Hypo-functioning in Depression. Vegetative/Somatic Aspects of Illness: sleep, appetite, libido, endocrine. Ventral Compartment (paralimbic cortical, subcortical and brainstem regions: HPA axis, insula, subgenual cingulate, and brainstem). Over-active in depression. Rostral Cingulate: important regulatory role in overall network facilitating interactions between dorsal and ventral components.

18. Manji et al., Nature Medicine 2001.

19. 5-HTT Gene Polymorphism Caspi et al., 2003. Why do stressful experiences lead to depression in some people but not in others? Individual’s response to environmental insults moderated by genetic makeup. In a prospective-longitudinal study of a representative birth cohort, a functional polymorphism in the promoter region of the serotonin transporter (5-HTT) gene was found to moderate influence of stressful life events on depression. Individuals with one or two copies of short allele of 5-HTT promoter polymorphism exhibited more depressive symptoms, diagnosable depression, and suicidality in relation to stressful life events than individuals homozygous for long allele.

20. 5-HTT Gene Polymorphism Caspi et al., 2003.

21. Sleep Neurophysiology Decreased REM latency, increased REM density, decreased non-REM sleep in 40% of outpatients and 80% of inpatients with MDD

22. Manji et al., Nature Medicine 2001.

23. Neuroendocrine factors Hypothalamic-pituitary-adrenal (HPA) axis implicated by observations that severely depressed patients fail to suppress corticotrophin- releasing factor (CRF) and serum cortisol in response to dexamethasone challenge (“suppression test”) and CSF samples of depressed patients contain increased CRF concentrations.

24. Endocrine Review: Cushing Syndrome Hypercortisolism Central obesity Muscle wasting Proximal muscle weakness (difficulty getting up from chair, going up stairs) Easy bruisability Moon facies Buffalo hump Weight gain Hirsutism, hyperglycemia Screening: 24 hour urine free Cortisol

25. Dexamethasone Suppression Test A normal result: decrease in cortisol levels upon administration of low-dose dexamethasone. Results indicative of Cushing's Disease (Pituitary adenoma causing increased ACTH production) involve no change in cortisol on low-dose dexamethasone, but inhibition of cortisol on high- dose dexamethasone. If the cortisol levels are unchanged by low- and high- dose dexamethasone then other causes of Cushing's Syndrome must be considered with further work-up needed.

26. Dexamethasone (continued) ACTHCortisolInterpretation Undetectable or lowNot suppressed by low or high doses. Adrenal Cushing syndrome. Adrenal mass requires surgery. Normal to elevatedNot suppressed by low or high doses. Ectopic ACTH. Chest/Abdominal CT. Mostly small cell lung carcinoma. Surgery or Ketoconazole if not a surgical candidate. Normal to elevatedNot suppressed by low, suppressed by high dose. Pituitary MRI to confirm Pituitary Cushing syndrome (Cushing’s Disease)

27. Serotonin Synthesis Serotonin Breaks down to 5-HIAA(5-Hydroxyindoleacetic acid) 5-hydroxytryptophan Converted by:Amino acid Decarboxylase Tryptophan Converted by:Tryptophan Hydroxylase

28. Stahl and Wise, CNS Spectrums 2008.

29. Dopamine Metabolism Steps Phenylalanine Tyrosine DOPA Dopamine Norepinephrine Phenylalanine Hydroxylase Tyrosine Hydroxylase (rate-limiting) DOPA Decarboxylase Dopamine Beta Hydroxylase Phenylamine N- Methyltransferase Epinephrine

30. Stahl and Wise, CNS Spectrums 2008.

31. Stahl and Wise, CNS Spectrums 2008

32. Desensitization of Neurotransmitter Receptors Stahl, Essential Psychopharmacology of Depression and Bipolar Disorder 2000. Amount of NT changes relatively rapidly after antidepressant introduced. Clinical effect is delayed, as is desensitization, or down regulation, of neurotransmitter receptors. Temporal correlation of clinical effects with changes in receptor sensitivity has given rise to hypothesis that changes in neurotransmitter receptor sensitivity may mediate clinical effects of antidepressant drugs (including tolerance to acute side effects of medications).

33. Monoaminergic Effects of Common ADs Stahl et. al., Prim Care Companion J Clin Psychiatry 2004.

36. MAOIs Stahl and Felker, CNS Spectrums 2008. Brain MAO-A must be inhibited for antidepressant efficacy to occur. This is the form of MAO that metabolizes 5-HT and NE. MAO-A, along with MAO-B, also metabolizes DA, but inhibition of MAO-A alone does not appear to lead to robust increases in brain DA levels since MAO-B can still metabolize DA.

37. MAOIs Stahl and Felker, CNS Spectrums 2008. In the presence of a large amount of DA derived from administration of a large dose of its precursor levodopa, selective MAO-B inhibition is sufficient to boost DA action in the brain. Two MAOIs, selegiline and rasagiline, when administered orally in doses selective for inhibition of MAO-B, are approved for use in patients with Parkinson’s disease, but not effective at these selective MAO-B doses as antidepressants.

38. MAOIs Stahl and Felker, CNS Spectrums 2008. Perhaps most important role of MAO-B in psychopharmacology is when it is inhibited simultaneously with MAO-A. In that case, there is robust triple monoaminergic boost of DA as well as 5- HT and NE. Theoretically would provide most powerful antidepressant efficacy across range of depressive symptoms. MAO-A plus B inhibition is one of the few therapeutic strategies available to increase DA in depression and, therefore, to treat refractory symptoms of diminished positive affect (theoretically) linked to DA deficiency.

39. MAOIs Stahl and Felker, CNS Spectrums 2008. Reversible inhibitors of monoamine (RIMAs) have potential of providing MAO-A inhibition with decreased risk of a tyramine reaction. If someone taking a RIMA eats aged cheese high in tyramine, as the tyramine is absorbed it will release NE; however, this released NE will chase the reversible inhibitor off the MAO-A enzyme, reactivating MAO-A in the intestine, liver, and sympathomimetic neurons, allowing destruction of the dangerous amines.

40. Phenelzine (Nardil, Nardelzine) Initial 45 mg/day in 3 divided doses; increase to 60-90 mg/day; after desired therapeutic effect achieved clinician should lower the dose as far as possible.

41. Tranylcypromine (Parnate) Initial 30 mg/day in divided doses; after 2 weeks increase daily dose by 10 mg every 1-3 weeks; max. 60 mg/day.

42. Isocarboxazid (Marplan) Initial 10 mg twice a day; increase daily dose by 10 mg every 2-4 days; dosed 2-4 times/day; max. 60 mg/day.

43. Seligiline Transdermal System (EMSAM) Initial 6 mg/24 hours; can increase by 3 mg/ 24 hours every 2 weeks. Maximum dose generally 12 mg/24 hours.

44. Moclobemide (Aurorix, Arima, Manerix) RIMA Initial 300 mg/day in 3 divided doses after a meal; increase dose gradually; maximum dose generally 600 mg/day; minimum dose generally 150 mg/day. At higher doses, moclobemide also inhibits MAO-B. Taking moclobemide after meals may minimize chances of interactions with tyramine.

47. Tertiary Amines Clomipramine (Anafranil) Imipramine (Tofranil) Trimipramine (Surmontil) Amitriptyline (Elavil) Doxepin (Sinequan) Two methyl groups at the end of the side chain.

48. Clomipramine (Anafranil) FDA Approved for OCD. Dose: Initial 25 mg/day; increase over 2 weeks to 100 mg/day to achieve desired therapeutic efficacy; max. dose generally 250 mg/day. 2D6 and 1A2 substrate. Monitoring of plasma drug levels!

49. Imipramine (Tofranil) Initial dosing: Initial 25 mg/day at bedtime; increase by 25 mg every 3-7 days. Usual therapeutic dose: 75- 100 mg/day once daily or in divided doses; gradually increase daily dose until desired efficacy is achieved. Max dose 300 mg/day 2D6 and 1A2 substrate. Monitoring of plasma drug levels! Metabolized to active metabolite, desipramine, by demethylation via CYP450 1A2.

50. Trimipramine (Surmontil) Initial dosing: 25 mg/day at bedtime; increase by 75 mg every 3-7 days. Usual therapeutic dose: 75 mg/day in divided doses; increase to 150 mg/day to achieve desired efficacy. Maximum 200 mg/day (hospitalized patients may receive up to 300 mg/day). Substrate for CYP450 2D6, 2C19, and 2C9. Half-life approx. 7-23 hrs.

51. Amitriptyline (Elavil) Initial dosing: 25 mg/day at bedtime; increase by 25 mg every 3-7 days. Usual therapeutic dose: 75 mg/day in divided doses; increase to 150 mg/day until desired efficacy is achieved. Maximum 300 mg/day. 2D6 and 1A2 substrate

52. Doxepin (Sinequan) Initial dosing: 25 mg/day at bedtime; increase by 25 mg every 3-7 days. Usual therapeutic dose: 75 mg/day; increase gradually until desired efficacy achieved; can be dosed once a day at bedtime or divided doses. Max dose: 300 mg/day. Substrate for 2D6, half-life approx. 8-24 hours.

53. Secondary Amines Desipramine (Norpramin, Pertofrane) Nortriptyline (Aventyl, Pamelor) Protriptyline (Vivactil) More potent in blocking the norepinephrine transporter.

54. Desipramine (Norpramin) Initial dosing: 25 mg/day at bedtime; increase by 25 mg every 3-7 days. Usual therapeutic dose: 75 mg/day once daily or in divided doses; gradually increase dose to achieve desired efficacy. Max. dose 300 mg/day. 2D6/1A2 substrate. Half- life approx. 24 hours. Active metabolite of imipramine. Monitoring of plasma drug levels!

55. Nortriptyline (Pamelor) Initial dosing: 10-25 mg/day at bedtime; increase by 25 mg every 3-7 days; can be dosed once daily or in divided doses (max. 300 mg/day). 2D6 substrate Nortriptyline is the active metabolite of Amitryptyline, formed by demethylation via 1A2. Half-life approx. 36 hours. Monitoring of plasma drug level well studied.

56. Protriptyline (Triptil, Vivactil) Initial dosing: 15 mg/day in divided doses; increase morning dose as needed; maximum dose 60 mg/day. 2D6 substrate Half-life approx. 74 hours.

57. Amoxapine (Ascendin) Derived from neuroleptic loxapine. Potent NRI Blocks postsynaptic dopamine receptors (has anti-psychotic activity) 2D6 substrate Half-life of parent drug 8 hours and active metabolites 24 hours. Initial dosing: 25 mg/day split 2- 3 times/day; increase gradually to 100 mg total either in split doses 2-3 times/day or single bedtime dose to achieve desired efficacy. Max. 400 mg/day (inpatient: 600).

58. Maprotiline (Ludiomil) Identical side chain to secondary amines (potently blocks norepinephrine transmitter). 2D6 substrate, 51 hr. mean half life, peak plasma concentration 8-24 hours. Initial 25 mg/day at bedtime; increase by 25 mg every 3-7 days. Usual therapeutic dose: 75 mg/day; after 2 weeks increase dose gradually by 25 mg/day to achieve desired efficacy; max. generally 225 mg/day.

59. Tricyclics: Potentially Fatal in Overdose! Anticholinergic effects: altered mental status (e.g., agitation, confusion, lethargy, etc.), resting sinus tachycardia, dry mouth, mydriasis (pupil dilation), fever Cardiac effects: hypertension (early /transient, should not be treated), tachycardia, orthostasis and hypotension, arrhythmias (such as ventricular tachycardia and ventricular fibrillation, most serious consequence)/ECG changes (prolonged QRS, QT and PR intervals) CNS: syncope, seizure (convulsions), coma, myoclonus, hyperreflexia Pulmonary effects: hypoventilation (resulting from CNS depression) Gastrointestinal effects: decreased (or absent) bowel sounds Metabolic Acidosis Treatment: Supportive with ICU Monitoring. Role for Sodium Bicarbonate: Tricyclics are highly protein bound, become less bound in more acidic conditions. By reversing acidosis, protein binding increases /bioavailability decreases. Alternative explanation: sodium load helps reverse Na+ channel blocking effects of TCA.

61. Fluoxetine (Prozac) FDA approved for: MDD, OCD, Premenstrual dysphoric disorder, Bulimia nervosa, Panic disorder, Bipolar depression (in combination with olanzapine [Symbyax]) 5HT2C antagonism could contribute to agitation, anxiety, undesirable activation (especially early in treatment) Initial dose 20 mg/day, wait a few weeks to assess drug effects before increasing. Maximum dose generally 80 mg/day.

62. Fluoxetine (Prozac) Active metabolite (norfluoxetine) has 2 weeks half-life Parent drug has 2-3 day half life Inhibitor of CYP450 2D6 and 3A4 May displace highly protein bound drugs such as Warfarin

63. Paroxetine (Paxil and Paxil CR*) FDA Approved for: MDD *, OCD, Panic Disorder *, Social Anxiety Disorder *, PTSD, GAD, PMDD (only CR) Mild anticholinergic actions, may have mild norepinephrine reuptake blockade MDD dose 20-50 mg/day (25-62.5 CR) Higher dose for anxiety disorders Dosage increments: increase by 50% once a week to achieve desired therapeutic efficacy. Withdrawal effects: many patients tolerate 50% dose reduction for 3 days then another 50% reduction for three days, then stop. Half life: 24 hours Inhibits CYP450 2D6, may displace warfarin

64. Sertraline (Zoloft) FDA approved: MDD, PMDD, Panic disorder, PTSD, Social anxiety disorder, OCD Some ability to block dopamine reuptake pump Mild antagonist actions at sigma receptors Generally does not elevate prolactin

65. Sertraline (Zoloft) Dosage: 50 mg/day May increase weekly to max of 200 mg/day Parent drug has 22-36 hour half-life, metabolite half- life 62-104 hours Inhibits 2D6 and 3A4 (weakly at low doses)

66. Fluvoxamine (Fluvox) FDA approved for OCD Has antagonist properties at sigma 1 receptors – may explain potential advantages in psychotic depression and delusional depression Dosage range 100-300 mg/day for OCD: initial 50 mg/day then increase every 4-7 days Parent drug has 9-28 hour half-life Inhibits 3A4, 1A2, 2C9/2C19

67. Enantiomers Burke and Kratochvil, Prim Care Companion J Clin Psychiatry 2004. Stereoisomers have same chemical structure but different spatial arrangement of substituent groups around chiral center (e.g. carbon atom) Enantiomers = non-superimposable mirror image (like R and L hand) Rotate plane-polarized light (+/−) by equal amounts but in opposite directions

68. Citalopram (Celexa) FDA approved for Depression Mild antagonist actions at H1 histamine receptors Inactive R entantiomer may interfere with therapeutic actions of active S enantiomer at serotonin reuptake pumps Initial dose 20 mg/day, increase 20 mg/day weekly until desired efficacy. Max usually 60 mg/day

69. Escitalopram (Lexapro) 10 mg of escitalopram may be comparable in efficacy to 40 mg of citalopram with fewer side effects Mean terminal half-life 27-32 hours Steady-state plasma concentrations achieved within 1 week No significant actions on CYP450 enzymes

70. Venlafaxine (Effexor XR) SNRI FDA Approved for Depression, GAD, Social Phobia, Panic disorder Usual dose: 75-225 mg/day (start at 37.5 mg once daily for a week, if tolerated increase by 75 mg every four days until desired efficacy reached. Max dose generally 375 mg/day. Withdrawal symptoms upon discontinuation: taper down slowly!

71. Duloxetine (Cymbalta) SNRI FDA approved for MDD, DPNP Initial 40 mg/day in 1-2 doses; can increase to 60 mg/day if necessary; max. 120 mg/day Elimination half-life 12 hours Metabolized mainly by 2D6 and 1A2 Inhibits 2D6 (clinically significant)

72. Desvenlafaxine (Pristiq) SNRI FDA approved for depression, usual dose 50 mg/day Unique feature: Metabolism primarily by conjugation in the liver and, to a lesser extent, oxidative metabolism (independent of CYP 2D6)

73. Bupropion Extended Release (Wellbutrin XL) NDRI FDA approved for MDD (Bupropion, Bupropion SR and Bupropion XL) and Nicotine Addiction (Bupropion SR) Usual adult target dose for Wellbutrin XL is 300 mg/day (given once daily in the morning). Dosing should begin at 150 mg/day given as a single daily dose. If 150-mg initial dose is adequately tolerated, an increase to the target dose (300-mg/day), given as once daily, may be made as early as day 4 of dosing. Should be an interval of at least 24 hours between successive doses. Max dose: 450 mg/day Inhibits 2D6

74. Mirtazapine (Remeron) Alpha 2 antagonist; NaSSA (noradrenaline and specific serotonergic agent); dual serotonin and norepinephrine agent. FDA approved for MDD, usual dosage 15-45 mg.day Blocks alpha 2 adrenergic presynaptic receptor (increase NE neurotransmission) Blocks alpha 2 adrenergic presynaptic receptor on serotonin neurons, increasing serotonin transmission Blocks 5HT2A (anxiolytic, sleep restoring, no sexual dysfunction), 5HT2C (anxiolytic, side effect of weight gain) and 5HT3 (no GI problems or nausea) serotonin receptors and H1 receptors (anxiolytic, weight gain, drowsiness) Half-life 20-40 hours

75. Trazodone (Desyrel) SARI (serotonin 2 antagonist/reuptake inhibitor) FDA approved for depression Metabolized by 3A4 Bi-phasic half-life; first phase 3-6 hours and second phase 5-9 hours For depression monotherapy, initial 150 mg/day in divided doses; can increase every 3-4 days by 50 mg/day as needed; max. 400 mg/day (outpatient) or 600 mg/day (inpatient) split into two daily doses For insomnia, initial 25-50 mg at bedtime; increase as tolerated usually to 50-100 mg/day

77. Trazodone ER (Oleptro) Recommended starting dose of Oleptro is 150 mg once daily in adults. Dose may be increased by 75 mg/day every three days (i.e., start 225 mg on therapy Day 4). Maximum daily dose should not exceed 375 mg.

78. Stahl et. al., Prim Care Companion J Clin Psychiatry 2004.

80. Serotonin Syndrome Clinical triad of abnormalities: Cognitive effects: agitation, headache,hypomania, mental confusion, hallucinations, coma Autonomic effects: sweating, shivering, hyperthermia, hypertension, tachycardia, nausea, diarrhea Somatic effects: tremor, myoclonus (muscle twitching), hyperreflexia (as manifested by clonus) Treatment: stop the offending agent! Supportive care and treat hyperthermia/autonomic instability. Benzodiazepines for myoclonus and agitation. Role for cyproheptadine.

81. Suicidality and Anti-depressant use FDA Black Box warning: Suicidality and Antidepressant use in adolescents (under 19) and young adults (19-24).

83. Antidepressant Discontinuation and Risk of Suicide Attempt Valuck et al., JCP 2009. Retrospective, Nested Case-Control Study After adjusting for confounding due to depression severity, comorbidities and other medications, antidepressant use showed protective effect for suicide attempt (OR = 0.62, P <.001). Antidepressant Discontinuation had a significant risk for suicide attempt compared to prior therapy (OR = 1.61, P <.05). Antidepressant initiation had highest risk for suicide attempt (OR = 3.42, P <.05), followed by titration (titration up, OR = 2.62 and down, OR = 2.19; P <.05). Recommendation: patients should be closely monitored during these periods!

85. Thase et al., Depression and Anxiety 2000.

86. Strategies for Treatment-Resistant Depression Nelson, JCP 2007. Switching Combination or Augmentation Advantages: improved compliance, reduced medication cost, fewer drug interactions Combination: add another antidepressant, typically from different class Augmentation: add second pharmacologic agent not generally used as antidepressant, such as T3 (Cytomel) Advantages: rapid response, No titration necessary, initial improvements maintained

87. Strategies for Treatment-Resistant Depression Nelson, JCP 2007. Bridging: addition of 2 nd agent to enhance response. If patient does well: first medication withdrawn and continue patient on second medication.

90. Papakostas, CNS Spectrums 2009.

91. Heroic Combos from Stahl’s Essential Psychopharmacology, 2009. 1: High dose venlaxafine + mirtazapine = California rocket fuel 2: High dose venlaxafine + NDRI (bupropion) 3: High dose venlaxafine + NRI (selective reboxetine or a nonselective TCA such as desipramine, maprotilene, nortriptyline, or protriptyline) 4: High dose venlaxafine + stimulant (e.g. d-amphetamine, methylphenidate, phentermine, or diethylpropion could also include direct-acting dopamine agonists such as pramipexole)

93. 5: Venlaxafine + SARI 6: Mirtazapine + SSRI 7: Mirtazapine + NRI (reboxetine) 8: Mirtazapine + NDRI (bupropion) 9: Mirtazapine + stimulant 10: SSRI + NRI (selective reboxetine) 11: SSRI + NDRI (bupropion) 12: SSRI + stimulant 13: SARI + NDRI (bupropion) Heroic Combos from Stahl’s Essential Psychopharmacology, 2009.

94. Aronson et al., Arch. Gen. Psychiatry 1996.

96. Lithium Augmentation Bauer et al., Canadian Journal of Psychiatry 2003.

98. Lithium Augmentation Bauer et al., Canadian Journal of Psychiatry, 2003.

99. Modafanil (Provigil) Stahl, JCP 2002. Neurotransmitters (hypocretin 1 and 2, orexin A and B) in lateral hypothalamus mediate aspects of sleep and arousal. Modafanil increases neuronal activity in wake promoting hypothalamic neurons and decreases activity in sleep promoting neurons. Dosage: 100 mg/day to 200 mg/day Former NBA player Eric “Sleepy” Floyd

100. Modafanil (Provigil) Rare cases of SJS (Stevens Johnson Syndrome), TEN (Toxic Epidermal Necrolysis), DRESS (Drug Rash with Eosinophilia and Systemic Symptoms). Discontinue medication at first sign of rash. Rare cases of multi-organ hypersensitivity. Former NBA player Eric “Sleepy” Floyd

102. References American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders DSM-IV-TR Fourth Edition (Text Revision). American Psychiatric Publishing, Inc.; 4th edition (June 2000). Aronson R., Offman H.J., Joffe R.T., Naylor D. Triiodothyronine Augmentation in the Treatment of Refractory Depression: A Meta-Analysis. Arch Gen Psychiatry 53: 842-848, 1996. Bauer M., Adli M., Baethge C., Berghofer A., Sasse J., Heinz A., Bschor T. Lithium Augmentation Therapy in Refractory Depression: Clinical Evidence and Neurobiological Mechanisms. Can J Psychiatry 48, 440-448, 2003. Burke W.J., Kratochvil C.J., Stereoisomers in Psychiatry: The Case of Escitalopram. Prim Care Companion J Clin Psychiatry 4: 20-24, 2002. Caspi A., Sugden K., Moffitt T.E., Taylor A., Craig I.W., Harrington H., McClay J., Mill J., Martin J., Braithwaite A., Poulton R. Influence of Life Stress on Depression: Moderation by a Polymorphism in the 5-HTT Gene. Science 301: 386-389, 2003. Cassano P., Lattanzi L., Soldani F., Navari S., Battistini G., Gemignani A., Cassano G.B. Pramipexole in Treatment-Resistant Depression: An Extended Follow-Up. Depression and Anxiety 20: 131-138, 2004.

103. References Hammad T.A., Laughren T., Racoosin J. Suicidality in Pediatric Patients treated with antidepressant drugs. Archives of General Psychiatry 63: 332-339, 2006. Manji H.K., Drevets W.C., Charney D.S. The cellular neurobiology of depression. Nature Medicine 7: 541-547, 2001. Mayberg H.S. ”Limbic-Cortical Dysregulation: A proposed model of Depression.” In: Salloway S., Malloy P., Cummings J.L. (Eds.). The Neuropsychiatry of Limbic and Subcortical Disorders (pp. 167-177). American Psychiatric Press, Inc. Washington, D.C., London, England (1997). Nelson J.C., Managing Treatment-Resistant Major Depression. J Clin Psychiatry 64 (supplement 1): 5-12. Nelson J.C., “Tricyclic and Tetracyclic Drugs.” In: Schatzberg A.F. and Nemeroff C.B., Eds. Textbook of Psychopharmacology, Fourth Edition (pp.263-287). Washington, D.C: American Psychiatric Publishing, 2009. Papakostas G.I., Switching Antidepressants vs. Conventional Augmentation Strategies. CNS Spectrums 14 (Supplement 4): 11-14, 2009. Patterson W.M., Dohn H.H., Bird J., Patterson G.A. Evaluation of suicidal patients: The SAD PERSONS Scale. Psychosomatics 24: 343-349, 1983.

104. References Rush J.A., Trivedi M.H., Wisniewski S.R., Nierenberg A.A., Stewart J.W., Warden D., Niederehe G., Thase M.E., Lavori P.W., Lebowitz B.D., McGrath P.J., Rosenbaum J.F., Sackeim H.A., Kupfer D.J., Luther J., Fava M. Acute and Longer-Term Outcomes in Depressed Outpatients Requiring One or Several Treatment Steps: A STAR*D Report. Am. J. Psychiatry 2006; 163: 1905-1917. Stahl S.M. Essential Psychopharmacology of Depression and Bipolar Disorder. Cambridge University Press, 2000. Stahl S.M., Pradko J.F., Haight B.R., Modell J.G., Rockett C.B., Learned- Coughlin S. A Review of the Neuropharmacology of Buproprion, a Dual Norepinephine and Dopamine Reuptake Inhibitor. Prim Care Companion J Clin Psychiatry 6: 159-166, 2004. Stahl SM, Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. Cambridge (UK), Cambridge University Press; Third edition (2008). Stahl S.M. and Felker A. Monoamine Oxidase Inhibitors: A Modern Guide to an Unrequited Class of Antidepressants. CNS Spectrums 13: 855-70, 2008.

105. References Stahl S.M., Awakening to the Psychopharmacology of Sleep and Arousal: Novel Neurotransmitters and Wake-Promoting Drugs. J. Clin. Psychiatry 63: 467-468, 2002. Stahl S.M., Selective Histamine H1 antagonism: Novel Hypnotic and Pharmacologic Actions Challenge Classical Notions of Antihistamines. CNS Spectrums 13: 1-12, 2008. Stahl S.M., Wise D.D. The Potential of a Corticotropin Releasing Factor-1 Antagonist in Psychiatric Disorders. CNS Spectrums 13: 467- 483, 2008. Stahl S.M., Essential Psychopharmacology: The Prescriber’s Guide (Antidepressants), Cambridge University Press; 3rd edition, 2009.

106. References Stahl S.M., Mechanism of Action of Trazodone: A Multifunctional Drug. CNS Spectrums 14: 536-546, 2009. Stahl, SM. Enhancing Outcomes from Major Depression: Using Antidepressant Combination Therapies with Multifunctional Pharmacologic Mechanisms from the Initiation of Treatment. CNS Spectrums 15: 79-94, 2010. Thase M.E., Friedman E.S., Howland R.H. Venlafaxine and Treatment- Resistant Depression. Depression and Anxiety 12 (supplement 1): 55- 62, 2000. Valuck R.J., Orton H.D., Libby A.M. Antidepressant Discontinuation and Risk of Suicide Attempt: A Retrospective, Nested Case Control Study. Journal of Clinical Psychiatry 79: 1069-1077, 2009.