1. Antidepressants

2. 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

3. 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)

4. 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

5. Pathophysiology of Major Depression
The neurotrophic hypothesis
The monoamine hypothesis

6. 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

7. 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:
©2012 by The Royal Society

8. 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)

9. 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

10. 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

11. 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

12. 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)

13. 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

14. 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

15. 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)

16. 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

17. 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

18. 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)

19. 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

20. 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)

21. 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

22. 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

23. 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

24. 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

25. 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)

26. 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

27. 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

28. 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

29. 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

30. 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

31. 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)

32. 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

33. 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

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

35. 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

36. 5-HT2 antagonists- Clinical uses
Depression: Mirtazapine can be advantagous in patients with depression having sleep difficulties
Low doses of trazodone ( mg) have been used widely both alone and concurrently with SSRIs or SNRIs to treat insomnia

37. 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

38. 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

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