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  1. 1. Mechanism of Action Classes of Antidepressant MedicationsClinical Effects and Side Effects
  2. 2. Things I always wanted to know aboutdepression, but I forgot to ask
  3. 3. Response = 50% improvement ofsymptoms In the past decades the goal of treatment in depression was a response. Now the goal of treatment in depression is remission and recovery.
  4. 4. Remission vs. Recovery Remission: Patient is symptom free for 4-9 months. Recovery: Patient is symptom free for more than 12 months.
  5. 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 monotherapy remitted. 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. 6. Relapse vs. RecurrenceWhat is a relapse? – Getting worse during the remission phaseWhat is a recurrence? – Getting worse during recovery phase
  7. 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. 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. 9. Antidepressants - Actions
  10. 10. Antidepressants: complex drugs Jules Angst(who discovered the antidepressant properties of Imipramine) stated in 1961: “The basis for the antidepressant effect of imipramine has not yet been elucidated, although more than three years have passed since its introduction.” Today after 50 years from its introduction we continue to discover new mechanisms of action of antidepressant drugs. These are the known mechanisms through which antidepressants exert their 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. 11. Monoamine Hypothesis Depression is due deficiency of monoamines: serotonin, dopamine or norepinephrine
  12. 12. All antidepressants (except MAO inhibitors) blockmonoamine transporter proteins Serotonin Transporter(SERT) Norepinephrine Transporter(NET) Dopamine Transporter(DAT)
  13. 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. 14. What is Neurotrophin Hypothesis? The reason why antidepressants work may not be the fact that they increase serotonin, dopamine or norepinephrine, but BDNF. BDNF is produced by the neurons and is encoded by a gene on chromosome 11. BDNF MOLECULE encoded on CHROMOSOME 11
  15. 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. 16. BDNF promotes formation of dendritic spinesthat help the neuron respond to the environment Axons usually form synapses with dendrites. In order to form a synapse the dendrite on the receiving neuron develops tiny hair-like growths known as spines. In a functional synapse that is extensively used, the spines develop into new dendrites.
  17. 17. BDNF Increases Dendritic Arborization
  18. 18. Low BDNF - depressed mood andsuicidal behavior
  19. 19. Antidepressant Classes Serotonin Selective Reuptake Inhibitors(SSRIs) Serotonin Norepinephrine Reuptake Inhibitors(SNRIs) Norepinephrine and Dopamine Reuptake Inhibitors(NDRIs) Selective Norepinephrine Reuptake Inhibitors(NRIs) Alpha 2 Antagonists as serotonin and norepinephrine Disinhibitors(SNDIs) Serotonin Antagonist/Reuptake Inhibitors(SARIs) Tricyclic Antidepressants(TCA) Monoamine Oxidase Inhibitors(MAOI)
  20. 20. Psychopharmacologically speaking there areonly two classes of depressions
  21. 21. SSRIs
  22. 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 for depression. It was approved for social phobia and OCD. In other countries it is being used for depression. Three agents come in CR form: Fluoxetine, Paroxetine and Fluvoxamine. All are generic except Escitalopram and the CR preparations.
  23. 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. 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. 25. Norepinephrine and DopamineReuptake Inhibitors(NDRIs) One drug: Bupropion FDA indication: MDD, smoking cessation and SAD. Off label use: depression in cardiac patients, adjunct to SSRIs (for depressed mood as well as to counteract sexual side effects), substance abuse problems, ADHD and weight loss. Mechanism of Action: mild dopamine reuptake inhibitor, norepinephrine reuptake inhibitor (via its metabolite hydroxybupropion). Adverse effects: 4/1000 risk for seizure disorder in immediate-release formulations (doses higher than 450 mg/day) and 1/1000 in sustained release formulations(identical to all other antidepressants).
  26. 26. Selective Norepinephrine ReuptakeInhibitors(NRIs) Two drugs: Atomoxetine and Reboxetine(not approved in US). Mechanism of Action: Block norepinephrine transportes. In the prefrontal cortex there are very few dopamine transporters. Norepinephrine transporters dispose of both norepinephrine and dopamine. For this reason when the norepinephrine transporters are blocked the levels of both NE and DA are increased. Atomoxetine (Strattera) has the FDA indication for ADHD, but off label it is used as antidepressant.
  27. 27. Alpha 2 Antagonists as Serotonin andNorepinephrine Disinhibitors(SNDIs) One drug: Mirtazapine FDA indication: MDD Off label uses: panic d/o, GAD, negative symptoms of schizophrenia, anti-nausea medication in chemotherapy patients(Kim 2008)and post operative nausea(Chen 2008). In STAR*D trial the combination of Mirtazapine(average dose 36 mg/day) with Venlafaxine (average dose 210 mg/day) resulted in remission of 13% of patients who failed three consecutive antidepressant trials(McGrath 2006). Mechanism of action: Blocks alpha 2 adrenergic receptors presynaptically(autoreceptors) on noradrenergic and serotonergic neurons, leading to disinhibition of serotonin and norepinephrine. In addition, mirtazapine blocks 5HT2A, 5HT2C and 5HT3 postsynaptically.
  28. 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. 29. Tricyclic Antidepressants(TCA) Efficacy: Second or third line agents for MDD, Panic d/o, OCD (FDA approved Clomipramine), Pain Syndromes, Migraine prophylaxis, Enuresis (FDA approved Imipramine). Side Effects: dry mouth, urinary retention, constipation, blurred vision, confusion, weight gain, sedation, sexual dysfunction, orthostasis, tachycardia and cardiac conduction abnormalities. Drug interactions: TCA increase warfarin levels, cimetidine increases TCA levels, clonidine – hypertensive crises(avoid), oral contraceptives – increase TCA levels, SSRIs increase TCA levels, quinidine with TCA- increase in arrhythmias(avoid), L-dopa decreases TCA levels, sympathomimetics with TCAs – risk for arrhythmia, HTN, tachycardia.
  30. 30. MAO Inhibitors (MAOI)  Efficacy: Third line agents for MDD, second line for Parkinson’s 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 Parkinson’s 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. 31. Antidepressants During Pregnancy(damned if you do, damned if you don’t))
  32. 32. Augmentation Strategies
  33. 33. Estradiol augmentation of antidepressantaction Estrogen has neurotrophic properties especially in the hypothalamus and hippocampus. During the early phase of the cycle estradiol level rises and induces dendritic spine formation and synaptogenesis. In the second half of the cycle (estradiol decreases and progesteron increases) leading to removal of dendritic spines and synapses.
  34. 34. T3/T4 augmentation of antidepressants(in thyroid deficiency)
  35. 35. Lithium increases the efficacy ofantidepressants(lithium augmentation)
  36. 36. L-5-methyl-tetrahydrofolate(MTHF) MTHF(unlike folate) crosses the BBB and activates the enzymes that lead to the formation of NE, DA and 5HT. These are the rate limiting enzymes such as triptophan hydroxilase(5HT)and thyrosine hydroxilase(DA and NE).
  37. 37. Vagus Nerve Stimulation The vagus nerve connects with the neurotransmitter centers in the brainstem(locus coeruleus and raphe nuclei). A pacemaker -like device is implanted in the chest wall with an implanted lead wrapped around the vagus nerve in the neck area. The device delivers pulses to the vagus nerve, which in turn boost monoamine neurotransmission.
  38. 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 and amygdala, giving a triaminergic boost.
  39. 39. Deep Brain Stimulation Effective for the treatment of motor complications in Parkinson’s disease and is now used in some centers for treatment resistant depression. Consists of a battery -powered pulse generator implanted in the chest wall like a pacemaker. One or two electrodes are implanted into the subgenual area of ACC .
  40. 40. Putative New Generationantidepressants Corticotropin-Releasing Hormone Receptor Antagonists(CRH1, CRH2) Vasopresin Receptor Antagonists(V1A, V1B) Glucocorticoid Receptor Antagonists(GR, MR) Agomelatine Glutamate Blockers(AMPA blockers, NMDA blockers) Neuropeptides(substance P, Galanin, Orexigenic Peptides) GSK 3 inhibitors Neurogenesis Enhancers(BDNF, GDNF) Beta 3 agonists
  41. 41. Glucocorticoid Receptor Antagonists Several reports suggested that Mifeprestone (RU-486) was beneficial in MDD with psychotic features (DeBattista et al. 2006)
  42. 42. Agomelatine
  43. 43. Beta 3 Agonists
  44. 44. Ketamine and other Glutamate Blockers Ketamine 0.5 mg/Kg intravenously administered to patients with major depression was found to exert a rapid (2 hours) postinfusion antidepressant effect lasting about a week(Zarate et al. 2006).
  45. 45. "The art of medicine consistsof amusing the patient whilenature cures the disease." Voltaire, French philosopher