1.Mechanism of ActionClasses of AntidepressantMedicationsClinical Effects and Side Effects

2. Things I always wanted to know aboutdepression, but I forgot I did not know 3. Response = 50% improvement ofsymptoms In the past decades the goal of treatment indepression was a response. Now the goal of treatment in depression isremission and recovery. 4. Remission vs. Recovery Remission: Patient is symptom free for 4-9months. Recovery: Patient is symptom free for more than 12months. 5. STAR*D Study In a large NIMH study called Sequenced Treatment Alternatives to Relieve Depression(STAR*D) the goal of treatment was remission. Only 1/3 of patients on Citalopram monotherapyremitted. 2/3 of patients failed to remit to Citalopram alone. If we are talking response instead of remission 60- 70% of patients respond to SSRI monotherapy. 6. Relapse vs. RecurrenceWhat is a relapse? Getting worse during the remission phaseWhat is a recurrence? Getting worse during recovery phase 7. Remission rates in MDD Approximately one-third (33%) of depressed patients will remit during treatment with any SSRI monotherapy. Unfortunately, for those who fail to remit, the likelihood of remission with another antidepressant monotherapy goes down with each successive trial. Thus, after a year of treatment with four sequential antidepressants (from four different classes) taken for twelve weeks each, only two-thirds of patients will have achieved remission. 8. Common residual symptoms In patients who do not achieve remission(but achieve response), the most common residual symptoms are insomnia, fatigue, painful physical complaints, problems concentrating, and lack of interest. The least common residual symptoms are depressed mood, suicidal ideation, and psychomotor retardation. 9. Antidepressants - Actions 10. Antidepressants: complex drugs These are the known mechanisms through which antidepressants exerttheir actions: 1. Increase in monoamines 2. Increase in BDNF 3. Decrease in CRH 4. Increase of neurogenesis in hippocampus 5. Methylation of DNA(epigenetic factors) 6. Increase secretion of GDNF in glial cells 11. Monoamine Hypothesis Depression is due deficiency of monoamines: serotonin, dopamine or norepinephrine 12. All antidepressants (except MAO inhibitors) blockmonoamine transporter proteins Serotonin Transporter(SERT) Norepinephrine Transporter(NET) Dopamine Transporter(DAT) 13. In the Prefrontal Cortex Blocking NET Increases bothNorepinephrine and Dopamine In the human prefrontal cortex there are very few DAT. As a result dopamine diffuses outside of the synapse, accumulates in the prefrontal cortex and is eventually disposed of by NET. Thus drugs that block NET increase both Norepinephrine and Dopamine in the prefrontal cortex. 14. What is Neurotrophin Hypothesis? The reason why antidepressants work may not be thefact that they increase serotonin, dopamine ornorepinephrine, but BDNF. BDNF is produced by the neurons and is encoded by agene on chromosome 11. 15. BDNF Increases Dendritic Spines 16. Actions of BDNF-Sustains the viability of neurons (neuroprotection)-Increases dendritic arborization and the number of synapses.-BDNF gene is suppressed by stress (via cortisol).-Decreased BDNF levels lead to neuronal atrophy and neuronal death.- BDNF levels are low in depression,but increase with antidepressant treatment.- Exercise increases BDNF levels. 17. Low BDNF - depressed mood andsuicidal behavior 18. Antidepressant Classes Serotonin Selective Reuptake Inhibitors(SSRIs) Serotonin Norepinephrine Reuptake Inhibitors(SNRIs) Norepinephrine and Dopamine ReuptakeInhibitors(NDRIs) Selective Norepinephrine Reuptake Inhibitors(NRIs) Alpha 2 Antagonists as serotonin and norepinephrineDisinhibitors(SNDIs) Serotonin Antagonist/Reuptake Inhibitors(SARIs) Serotonin Partial Agonist Reuptake Inhibitor (SPARI) Tricyclic Antidepressants(TCA) Monoamine Oxidase Inhibitors(MAOI) 19. Psychopharmacologically speaking there areonly two classes of depressions 20. Serotonin Selective ReuptakeInhibitors (SSRIs) Six agents are in this class:Fluoxetine, Paroxetine, Sertaline, Fluvoxamine, Citalopramand Escitalopram. Fluvoxamine does not have an FDA indication fordepression. It was approved for social phobia and OCD. Inother countries it is being used for depression. Three agents come in CR form: Fluoxetine, Paroxetine andFluvoxamine. All are generic except the CR preparations. 21. SSRIs overview Efficacy(FDA approved) for: MDD (all except Fluvoxamine) OCD( all except Citalopram and Escitalopram) Social Phobia(Sertaline, Fluvoxamine, and Paroxetine) PTSD(Sertaline and Paroxetine) Bulimia(Fluoxetine) GAD(Paroxetine and Escitalopram) PMDD(Fluoxetine, Paroxetine CR and Sertaline) Side Effects: GI, decreased libido, delayed ejaculation, headaches and Insomnia/Somnolence. 22. Serotonin NorepinephrineReuptake Inhibitors(SNRIs) Four agents: Venlafaxine, Desvenlafaxine, Duloxetine and Milnacipran Efficacy(FDA approved) for: -Venlafaxine(MDD, GAD, Social Phobia) -Desvenlafaxine(MDD) -Duloxetine(MDD, GAD, neuropathic pain, fibromyalgia) -Milnacipran(fibromyalgia) Off label uses: Venlafaxine (ADHD) Duloxetine (stress urinary incontinence) Desvenlafaxine(vasomotor symptoms associated with menopause) 23. Norepinephrine and DopamineReuptake Inhibitors(NDRIs) One drug: Bupropion FDA indication: MDD, smoking cessation and SAD. Off label use: depression in cardiac patients, adjunct toSSRIs (for depressed mood as well as to counteract sexualside effects), substance abuse problems, ADHD and weightloss. Mechanism of Action: mild dopamine reuptakeinhibitor, norepinephrine reuptake inhibitor (via itsmetabolite hydroxybupropion). Adverse effects: 4/1000 risk for seizure disorder inimmediate-release formulations (doses higher than 450mg/day) and 1/1000 in sustained releaseformulations(identical to all other antidepressants). 24. Selective Norepinephrine ReuptakeInhibitors(NRIs) Two drugs: Atomoxetine and Reboxetine(notapproved in US). Mechanism of Action: Block norepinephrinetransportes. In the prefrontal cortex there are very fewdopamine transporters. Norepinephrine transportersdispose of both norepinephrine and dopamine. Forthis reason when the norepinephrine transporters areblocked the levels of both NE and DA are increased. Atomoxetine (Strattera) has the FDA indication forADHD, but off label it is used as antidepressant. 25. Alpha 2 Antagonists as Serotonin andNorepinephrine Disinhibitors(SNDIs) One drug: Mirtazapine FDA indication: MDD Off label uses: panic d/o, GAD, negative symptoms ofschizophrenia, anti-nausea medication in chemotherapypatients(Kim 2008)and post operative nausea(Chen 2008). In STAR*D trial the combination of Mirtazapine(averagedose 36 mg/day) with Venlafaxine (average dose 210mg/day) resulted in remission of 13% of patients who failedthree consecutive antidepressant trials(McGrath 2006). Mechanism of action: Blocks alpha 2 adrenergicreceptors presynaptically(autoreceptors) onnoradrenergic and serotonergic neurons, leading todisinhibition of serotonin and norepinephrine. Inaddition, mirtazapine blocks 5HT2A, 5HT2C and 5HT3postsynaptically. 26. Serotonin Antagonist/ReuptakeInhibitors(SARIs) Two agents: Trazodone, Nefazodone Both have FDA indication for MDD. Off label use: anxiety (Trazodone), PTSD (Nefazodone one of the most prescribed drugs for PTSD). Depression with co-morbid substance abuse (Nefazodone). Mechanism of Action: presynaptically blocks the serotonin transporters and 5HT1A postsynaptically blocks 5HT2A, 5HT2C Adverse effects: liver damage (risk 1/250,000 per patient/year) = If a quarter of a million patients were taking Nefazodone for a year , one patient would be expected to develop liver damage. 27. Serotonin Partial Agonist ReuptakeInhibitor (SPARI) Vilazodone (Viibryd) approved in January 2011.FDA approved for Major Depressive DisorderOff label used for Anxiety Mechanism of action:-blocks serotonin reuptake pumps-partial agonist at presynaptic somatodendritic 5HT 1ADosage:40 mg once daily with food (taken on empty stomach 50%reduced absorbtionSide effects: nausea, diarrhea, insomnia, rare hyponatremia 28. Tricyclic Antidepressants(TCA) Efficacy: Second or third line agents for MDD,Panic d/o, OCD (FDA approved Clomipramine), PainSyndromes, Migraine prophylaxis, Enuresis (FDA approvedImipramine). Side Effects: dry mouth, urinaryretention, constipation, blurred vision, confusion, weightgain, sedation, sexual dysfunction, orthostasis, tachycardia andcardiac conduction abnormalities. Drug interactions: TCA increase warfarin levels, cimetidineincreases TCA levels, clonidine hypertensive crises(avoid), oralcontraceptives increase TCA levels, SSRIs increase TCAlevels, quinidine with TCA- increase in arrhythmias(avoid), L-dopa decreases TCA levels, sympathomimetics with TCAs riskfor arrhythmia, HTN, tachycardia. 29. MAO Inhibitors (MAOI) Efficacy: Third line agents for MDD, second line for Parkinsons disease(Selegiline). FDA indications: treatment resistant depression. Selegiline(Emsam) was approved by the FDA in 2006 in the transdermal form for depression (oral Selegiline is not approved for depression). The Selegiline dilemma: Selegiline is a MAO-B inhibitor and in the doses used for Parkinsons disease (5-10 mg a day) has a low risk for hypertensive crises. Unfortunately for the treatment of depression higher doses (40-60 mg a day) are needed. At these high doses the drug affects both MAO-A and MAO-B and the risk for hypertensive crises is high. The transdermal Selegiline(Emsam) bypasses the gut and the liver and thus allows for use of higher doses with lower risk for hypertensive crises(below 60 mg a day). 30. Drug Interactions and AdverseEffects Risk of serious drug interactions is limited with SSRIs, except in twocircumstances: -Fatalities have been reported from serotonin syndrome when used inclose proximity with MAOI, even if the drugs were not usedconcurrently. -Inhibition of 2D6 enzyme by the SSRIs. Many drugs are metabolized by this enzyme, including TCA, type 1Cantiarrhythmic agents, some beta blockers, benztropine and manyantipsychotics.SSRIs inhibit 2D6, leading to increased plasma levels of other agents (8fold increase in TCA plasma levels have been reported when usedtogether). 31. Antidepressants During Pregnancy(damned if you do, damned if you dont) 32. T3/T4 augmentation of antidepressants(in thyroid deficiency) 33. Lithium increases the efficacy ofantidepressants(lithium augmentation) 34. L-5-methyl-tetrahydrofolate(MTHF) MTHF(unlike folate) crosses the BBB and activates the enzymes thatlead to the formation of NE, DA and 5HT. These are the rate limiting enzymes such as triptophanhydroxilase(5HT)and thyrosine hydroxilase(DA and NE). 35. Vagus Nerve Stimulation The vagus nerve connects with the neurotransmitter centers in thebrainstem(locus coeruleus and raphe nuclei). A pacemaker -like device is implanted in the chest wall with an implanted leadwrapped around the vagus nerve in the neck area. The device delivers pulses to the vagus nerve, which in turn boost monoamineneurotransmission. 36. Transcranial Magnetic Stimulation(TMS) Rapidly alternating current passes through a small coil placed over the scalp. This generates a magnetic field that induces an electrical current in the DLPFC. The affected neurons then signal other areas of the brain VMPFC andamygdala, giving a triaminergic boost. 37. Deep Brain Stimulation Effective for the treatment of motor complications in Parkinsons disease and is nowused in some centers for treatment resistant depression. Consists of a battery -powered pulse generator implanted in the chest wall like apacemaker. One or two electrodes are implanted into the subgenual area of ACC . 38. Putative New Generationantidepressants Corticotropin-Releasing Hormone ReceptorAntagonists(CRH1, CRH2) Vasopresin Receptor Antagonists(V1A, V1B) Glucocorticoid Receptor Antagonists(GR, MR) Agomelatine Glutamate Blockers(AMPA blockers, NMDA blockers) Neuropeptides(substance P, Galanin, OrexigenicPeptides) GSK 3 inhibitors Neurogenesis Enhancers(BDNF, GDNF) Beta 3 agonists 39. Glucocorticoid Receptor Antagonists Several reports suggested that Mifeprestone (RU-486) was beneficial in MDD with psychotic features (DeBattista et al. 2006) 40. Agomelatine 41. Beta 3 Agonists 42. Ketamine and other Glutamate Blockers Ketamine 0.5 mg/Kg intravenously administered to patients with majordepression was found to exert a rapid (2 hours) postinfusion antidepressanteffect lasting about a week(Zarate et al. 2006). 43. References: Stahls Essential Psychopharmacology, ThirdEdition, 2010 Textbook of Psychopharmacology, FourtEdition, Schatzberg, Nemeroff, 2010 Brain Protection in Schizophrenia, Mood andCognitive Disorders, Ritsner et al, 2010