1.Mechanism of ActionClasses of AntidepressantMedicationsClinical Effects and Side Effects

2. Things I always wanted to know aboutdepression, but I forgot to ask 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 Jules Angst(who discovered the antidepressant properties ofImipramine) stated in 1961: The basis for the antidepressant effectof imipramine has not yet been elucidated, although more thanthree years have passed since its introduction. Today after 50 yearsfrom its introduction we continue to discover new mechanisms ofaction of antidepressant 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. BDNF MOLECULE encoded on CHROMOSOME 11 15. Actions of BDNF-Sustains the viability of neurons.-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. 16. BDNF promotes formation of dendritic spinesthat help the neuron respond to the environmentAxons usually form synapses withdendrites.In order to form a synapse the dendriteon the receiving neuron develops tinyhair-like growths known as spines.In a functional synapse that isextensively used, the spines developinto new dendrites. 17. BDNF Increases Dendritic Arborization 18. Low BDNF - depressed mood andsuicidal behavior 19. 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) Tricyclic Antidepressants(TCA) Monoamine Oxidase Inhibitors(MAOI) 20. Psychopharmacologically speaking there areonly two classes of depressions 21. SSRIs 22. Serotonin Selective ReuptakeInhibitors (SSRIs) Six agents are in this class: Fluoxetine, Paroxetine,Sertaline, Fluvoxamine, Citalopram and 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 Escitalopram and the CRpreparations. 23. 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. 24. 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) 25. 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). 26. 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. 27. 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. 28. 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. 29. 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, urinary retention, constipation,blurred vision, confusion, weight gain, sedation, sexualdysfunction, orthostasis, tachycardia and cardiac conductionabnormalities. Drug interactions: TCA increase warfarin levels, cimetidineincreases TCA levels, clonidine hypertensive crises(avoid), oralcontraceptives increase TCA levels, SSRIs increase TCA levels,quinidine with TCA- increase in arrhythmias(avoid), L-dopadecreases TCA levels, sympathomimetics with TCAs risk forarrhythmia, HTN, tachycardia. 30. 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). 31. Antidepressants During Pregnancy(damned if you do, damned if you dont)) 32. Augmentation Strategies 33. Estradiol augmentation of antidepressantaction Estrogen has neurotrophic properties especially in the hypothalamus andhippocampus. During the early phase of the cycle estradiol level rises and induces dendriticspine formation and synaptogenesis. In the second half of the cycle (estradiol decreases and progesteron increases)leading to removal of dendritic spines and synapses. 34. T3/T4 augmentation of antidepressants(in thyroid deficiency) 35. Lithium increases the efficacy ofantidepressants(lithium augmentation) 36. 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). 37. 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. 38. 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. 39. 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 . 40. 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 41. Glucocorticoid Receptor Antagonists Several reports suggested that Mifeprestone (RU-486) was beneficial in MDD with psychotic features (DeBattista et al. 2006) 42. Agomelatine 43. Beta 3 Agonists 44. 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). 45. "The art of medicine consistsof amusing the patient whilenature cures the disease."Voltaire, French philosopher