Antidepressants

Introduction Worldwide, depression is a major cause of disability and premature death Depression is the most common of the affective disorders (defined as disorders of mood rather than disturbances of thought or cognition) In addition to the significant suicide risk, depressed individuals are more likely to die from other causes, such as heart disease or cancer

Introduction Depressive symptoms also can occur secondary to other illnesses such as hypothyroidism, Parkinson's disease, and inflammatory conditions For a diagnosis of major depressive disorder to be made, symptoms must be present for at least 2 weeks and must not be precipitated or influenced by a medical illness or medication Depression, in general, is classified as major depression (i.e., unipolar depression) or bipolar depression (i.e., manic depressive illness)

Introduction Individuals must possess at least five symptoms, one of which is either depressed mood OR diminished interest or pleasure in activities Change in appetite Change in sleep Low energy and decreased libido Poor concentration (or difficulty making decisions) Feelings of worthlessness or inappropriate guilt Psychomotor agitation or retardation Recurrent thoughts of suicide

Pathophysiology of Major Depression The neurotrophic hypothesis The monoamine hypothesis

Neurotrophic Hypothesis Depression appears to be associated with a drop in brain-derived neurotrophic factor (BDNF) levels in the cerebrospinal fluid and serum Antidepressant treatment blocks or reverses this neurotrophic factor deficit, and thereby reverses the atrophy and cell loss

Opposing actions of stress and antidepressants on brain-derived neurotrophic factor (BDNF) and neurogenesis. Opposing actions of stress and antidepressants on brain-derived neurotrophic factor (BDNF) and neurogenesis. Stress decreases and antidepressant treatment increases the expression of BDNF, as well as vascular endothelial growth factor (VEGF) in the dentate gyrus granule cell layer of the hippocampus. These changes in growth factor expression contribute to the regulation of neurogenesis by stress and antidepressants. The negative effects of stress are also mediated in part by interleukin-1 (IL-1). This model shows the proliferation of neural progenitor cells giving rise to new neurons in the adult hippocampus. Antidepressants influence both the proliferation and survival of new neurons via effects on BDNF and VEGF. See text for details. Duman R S , and Li N Phil. Trans. R. Soc. B 2012;367:2475-2484 ©2012 by The Royal Society

Monoamine hypothesis of depression The monoamine hypothesis of depression suggests that depression is related to a deficiency in the amount or function of cortical and limbic serotonin (5-HT), norepinephrine (NE), and dopamine (DA)

Monoamine hypothesis of depression The chronic activation of monoamine receptors by antidepressants appears to increase in BDNF transcription One of the weaknesses of the monoamine hypothesis is the fact that amine levels increase immediately with antidepressant use, but maximum beneficial effects of antidepressants are not seen for many weeks The time required to synthesize neurotrophic factors has been proposed as an explanation for this delay of antidepressant effects

Antidpressents Most antidepressants exert important actions on the metabolism of monoamine neurotransmitters and their receptors, particularly norepinephrine and serotonin The pharmacologic effects of any of the antidepressant drugs on neurotransmission occur immediately, whereas the time course for a therapeutic response occurs over several weeks It takes at least 2 weeks to produce significant improvement in mood "therapeutic lag", and maximum benefit may require up to 12 weeks or more

Antidpressents Long-term effects of antidepressant drugs evoke adaptive or regulatory mechanisms that enhance the effectiveness of therapy: Increased adrenergic or serotonergic receptor density or sensitivity Increased receptor-G protein coupling Increased cyclic nucleotide signaling Induction of neurotrophic factors Increased neurogenesis in the hippocampus Reduces the expression and activity of 5-HT or NE transporters in the brain

Selective Serotonin Reuptake Inhibitors (SSRIs) They are the most commonly prescribed group of antidepressants They specifically inhibit serotonin reuptake, having 300- to 3000-fold greater selectivity for the serotonin transporter as compared to the norepinephrine transporter Agents: Fluoxetine (Prozac®), paroxetine, sertraline, fluvoxamine, Citalopram, & Escitalopram (s-citalopram)

Selective Serotonin Reuptake Inhibitors (SSRIs) As a class, these medications have little or no affinity for cholinergic, β-adrenergic or histamine receptors and do not interfere with cardiac conduction They are well tolerated by patients who are especially sensitive to the anticholinergic and orthostatic effects of the TCAs and MAOIs

SSRIs- Clinical uses Major Depression: the primary indication Obsessive-compulsive disorder (OCD) (fluvoxamine, clomipramine) Panic disorder Generalized anxiety disorder Posttraumatic stress disorder (Sertraline and paroxetine) Social anxiety disorder (SAD): fluvoxamine, venlafaxine Premenstrual dysphoric disorder (fluxetine & sertraline) Bulimia nervosa (only fluoxetine) Premature ejaculation

SSRIs- ADEs GIT: nausea, GIT upset, diarrhea. GIT adverse effects usually emerge early in the course of treatment and tend to improve after the first week Sexual dysfunction: Loss of libido, delayed orgasm, or diminished arousal Management: dose reduction, drug holidays, use sildenafil to improve sexual function, replace the antidepressant (bupropion or mirtazapine)

SSRIs- ADEs Sleep disturbances: Fluoxetine is usually administered in the morning after breakfast as it precipitate or exacerbate restlessness, agitation, and sleep disturbances—side Discontinuation syndrome: Sudden/ abrupt discontinuation of short half-life SSRIs and having inactive metabolites (e.g. paroxetine and sertraline) Fluoxetine has the lowest risk of causing an SSRI discontinuation syndrome

SSRIs- ADEs Weight gain particularly paroxetine SSRIs have also been associated with extrapyramidal side effects, especially those with Parkinson’s disease There is an association of paroxetine with cardiac septal defects in first trimester exposures

Serotonin-Norepinephrine Reuptake Inhibitors Two classes of antidepressants act as combined serotonin and norepinephrine reuptake inhibitors: Selective serotonin-norepinephrine reuptake inhibitors (SNRIs) Tricyclic antidepressants (TCAs)

a) Selective Serotonin-Norepinephrine Reuptake Inhibitors Agents: venlafaxine, desvenlafaxine, and duloxetine & milnacipran* All SNRIs bind the serotonin (SERT) and norepinephrine (NET) transporters Unlike the TCAs, the SNRIs have little activity at adrenergic, muscarinic, or histamine receptors and, thus, have fewer of these receptor-mediated adverse effects than the TCA *Milnacipran is not used to treat depression. It is approved for the treatment of fibromyalgia

SNRIs- Clinical uses Depression: in patients in whom SSRIs are ineffective chronic joint and muscle pain: duloxetine Fibromyalgia: milnacipran Urinary stress incontinence (duloxetine in Europe) Off-label uses include autism, binge eating disorders, hot flashes (desvenlafaxine), pain syndromes, premenstrual dysphoric disorders, and post-traumatic stress disorders (venlafaxine)

I. SNRIs- ADRs SNRIs have many of the serotonergic adverse effects associated with SSRIs In addition, SNRIs may also have noradrenergic effects, including increased blood pressure and heart rate, and CNS activation, such as insomnia, anxiety, and agitation All the SNRIs have been associated with a discontinuation syndrome resembling that seen with SSRI discontinuation The SNRIs have relatively fewer CYP450 interactions than the SSRIs

II.Tricyclic Antidepressants (TCA) Agents: imipramine (the prototype drug), amitriptyline, clomipramine, doxepin , trimipramine, desipramine, nortriptyline, and protriptyline TCAs also block serotonergic, α-adrenergic, histaminic, and muscarinic receptors: associated with untoward effects of TCAs

II. TCA- Clinical uses Depression: that is unresponsive to more commonly used antidepressants )SSRIs or SNRIs) Panic disorder Control bed-wetting in children (older than 6 years) by causing contraction of the internal sphincter of the bladder (Imipramine)1 Treatment of migraine headache and chronic pain syndromes for which the cause of the pain is unclear (Amitriptyline) 1 At present, it is used cautiously because of the inducement of cardiac arrhythmias and other serious cardiovascular problems

II.TCA- ADRs Life-threatening arrhythmias Antimuscarinic SEs: Include: dry mouth ,constipation, urinary retention, blurred vision, and confusion are attributable Life-threatening arrhythmias The TCAs are class 1A antiarrhythmic agents ECG is indicated for patients with significant cardiac risk factors and older than age 50 years Combinations of TCAs with other class I antiarrhythmic agents can exert additive toxic effects on cardiac conduction

II.TCA- ADRs Sedation (H1 antagonism) : Often attenuates in the first weeks of treatment Usually administered at bedtime to minimize functional impairments At therapeutic doses, the TCA drugs lower the seizure threshold and at toxic doses can cause life-threatening seizures (especially Maprotiline)

TCA overdose If a patient is severely depressed, potentially suicidal, impulsive, or has a history of substance abuse, prescribing a relatively safe antidepressant agent with close clinical follow-up is appropriate

MAO inhibitors Agents: selegline, phenelzine, and tranylcypromine MAO exists in the human body in two molecular forms, known as type A and type B Norepinephrine and serotonin are preferentially metabolized by MAO-A. MAO-B is more likely to be involved in the catabolism of human brain dopamine

MAO inhibitors The MAO inhibitors inactivate the enzyme, permitting neurotransmitter molecules to escape degradation and, therefore, to both accumulate within the presynaptic neuron and leak into the synaptic space Selective MAO-A inhibitors are more effective in treating major depression than type B inhibitors

MAO inhibitors Despite their efficacy in treating depression, because of their risk for drug-drug and drug-food interactions, the MAO inhibitors are considered to be last-line agents in many treatment venues

MAO Inhibitors-Clinical use Depression: Reserved for treatment of depressions that resist therapeutic trials of the newer, safer antidepressants Selegiline is the first antidepressant available in a transdermal delivery system

MAO Inhibitors-ADRs Orthostatic hypotension, weight gain, edema, and sexual dysfunction are common during MAOI therapy Sexual SEs: highest rates are associated with the irreversible nonselective MAOIs (phenelzine and tranylcypromine)

MAO Inhibitors-D-D interactions Serotonin syndrome When compined with a serotonergic agent (SSRIs, SNRIs, and most TCAs) may result in a life-threatening It is caused by overstimulation of 5-HT receptors in the central gray nuclei and the medulla Most serotonergic antidepressants should be discontinued at least 2 weeks before starting a MAOI

MAO Inhibitors-D-D interactions Serious interaction with MAOIs occurs when an MAOI is combined with tyramine in the diet (e.g. smoked, aged, or pickled meat or fish, aged cheeses, etc) Can be minimized with a low-tyramine diet that begins several days before starting the MAOI & continues for 3-4 weeks after stopping the MAOI

Youdim et al. Nature Reviews Neuroscience 7, 295–309 (April 2006) | doi:10.1038/nrn1883

5-HT2 antagonists Agents: Nefazodone, Trazodone, mirtazapine and mianserin (not marketed in the U.S.) Inhibition of 5-HT2A receptors in both animal and human studies is associated with substantial antianxiety, antipsychotic, and antidepressant effects

5-HT2 antagonists- Clinical uses Depression: Mirtazapine can be advantagous in patients with depression having sleep difficulties Low doses of trazodone (50-100 mg) have been used widely both alone and concurrently with SSRIs or SNRIs to treat insomnia

I.5-HT2 antagonists- ADRs Sedation (trazodone & mirtazapine): Dose-related GIT SEs Priapism: uncommon but serious side effect requiring surgical intervention in one-third of the cases reported weight gain (mirtazapine) Nefazodone has been associated with hepatotoxicity, including rare fatalities and cases of hepatic failure requiring transplantation

II. Bupropion It acts as a weak dopamine and norepinephrine reuptake inhibitor to alleviate the symptoms of depression Bupropion has virtually no direct effects on the serotonin system Unlike the SSRIs, bupropion does not cause sexual side effects It does not block muscarinic, histaminergic, or adrenergic receptors

Bupropion- Clinical uses Depression Bupropion is approved as a treatment for smoking cessation