Drugs for Depressive Disorders

1. Drugs for Depressive Disorders Kaukab Azim, MBBS, PhD

2. Drug List

3. Classification of Depressive Disorders(from DSM IV text revision)

4. The Monoamine Hypothesis of Depression • This hypothesis suggests that depression is related to a deficiency in the amount or function of cortical and limbic serotonin and norepinephrine. • Evidence for this hypothesis includes the following: • Reserpine, which depletes monoamine stores in the CNS, is associated with depression in subset of patients. • There is an elevation of MAO-A in most brain regions of depressed patients. • Genetic studies indicate a functional polymorphism for the gene of serotonin transporter. Subjects who are homozygous for the s (short) allele may be more vulnerable to developing major depression in response to stress. • All available antidepressants appear to increase the levels of NE and/or 5-HT in the synaptic cleft.

5. The Dysregulation Hypothesis of Depression • This hypothesis suggests that depression is related to a failure of homeostatic regulation of neurotransmitter systems. • Evidence for this hypothesis includes the following: • Chronic (but not acute) administration of most antidepressants causes a down-regulation of postsynaptic CNS receptors (mainly beta-adrenergic and serotonergic). • Non pharmacological therapies of depression (like electroconvulsive therapy and REM sleep deprivation) cause a similar down-regulation of postsynaptic CNS receptors.

6. The Neuroendocrine Hypothesis of Depression Evidence for this hypothesis includes the following: • There is substantial evidence that nerve growth factors such as brain derived neurotrophic factor (BDNF) are critical in the regulation of neural plasticity and neurogenesis. • There is a reduction of BDNF associated with stress and pain. • BDNF directly infused into lateral ventricle of animals shows antidepressanteffects. • Depression and chronic stress states are associated with a substantial loss of volume in anterior cingulate and medial orbital frontal cortex. • Major depression is associated with a 5-10% loss of volume in the hippocampus. • Chronic (but not acute) administration of all antidepressants increases BDNF and is associated with an increased neurogenesis in the hippocampus. • ECT therapy and 24 hour sleep deprivation stimulate BDNF levels andhippocampus neurogenesis in animalmodels.

7. Pharmacology of Antidepressants Mechanism of action Short-term mechanisms The molecular action of most antidepressants is an increase availability of NE and/or 5-HT in the synaptic cleft of brain neurons, or an altered response of these monoamine receptors. This is most likely due to the following mechanisms: • Tricyclic antidepressants (TCADs) Blockade of reuptake of 5-HT and NE. • Monoamineoxidaseinhibitors Non selective inhibition of both MAO A and MAO B (Phenelzine). Selective inhibition of MAO B. (Selegiline). • Atypical ( also called heterocyclic) antidepressants (HEADS) Mechanisms are often unclear (see specific agents below) but in most cases the final result is an effect on monoamines or monoamine receptors. • Selective serotonin reuptake inhibitors (SSRIs) Selective blockade of the reuptake of 5-HT (at therapeutic doses about 80% of the activity of the transporter is inhibited) • Selectiveserotonin & norepinephrinereuptakeinhibitors(SNRIs) Blockade of the reuptake of 5-HT and NE.

8. Pharmacology of Antidepressants Mechanism of action Long-term mechanisms • Over time the increase availability of monoamines in the synaptic cleft likely causes a down-regulation of postsynaptic CNS receptors (mainly adrenergic and serotonergic). This occurs after 1-4 weeks of treatment when the therapeutic effect becomes evident. • Long term changes ultimately increase BDNF which increases neurogenesis, mainly in the hippocampus.

9. Pharmacology of Antidepressants Pharmacological effects • All available antidepressants are equally effective in the general depressed patient population. • All antidepressants have the same delayed onset (1-4 weeks) of therapeutic effects. • Some central and many peripheral effects of antidepressants result from blockade of serotonergic, adrenergic, cholinergic and histaminergic receptors (see table in next slide). Pharmacokinetics and administration • Variable oral bioavailability (0.25-0.70) • High or very high Vd. • Extensive metabolism by the liver (some metabolites are active). • Half-lives are long (8-36 hours). Fluoxetine has a half life of about 50 hours and an active metabolite with a half life of about 10 days. Administration: PO, IM , IV, transdermalpatch (selegiline).

10. Reuptake and Blocking Activity and Receptor Blocking Activity of Antidepressants

11. Heterocyclic (atypical) AntidepressantTRAZODONE Mechanism of action • The drug is thought to act primarily as an antagonist at 5-HT2-A and 5-HT2-C presynaptic receptors, so increasing serotonin release. Adverse effects • Drowsiness (up to 40%, likely related to blockade of 5-HT2 A, alpha-1 and H1 receptors). • Postural hypotension • Xerostomia(up to 30%) • Priapism, sexual dysfunctions. Therapeutic uses • Depression (as a second choice drug, mainly in patients with agitation and insomnia). • As an unlabeled hypnotic, since it is not associated with tolerance or dependence.

12. Heterocyclic (atypical) AntidepressantBUPROPION Mechanism of action • It is still poorly understood. It stimulates the release and blocks the reuptake of NE and DE. The drug is closely related to diethylpropion(an amphetamine-like drug). • The drug has virtually no direct effects on the serotonin system. Adverse effects • Insomnia (up to 30%), tremor (up to 20%), • Seizures(dose-dependenteffect). • Appetite reduction, weight loss (up to 28 %) • Xerostomia, constipation (.10%) Contraindications • Current or past epilepsy • Conditions predisposing to a low threshold for seizures (head trauma, alcohol misuse, diabetes, etc) • Use of certain drugs (theophylline, neuroleptics, glucocorticoids) Therapeutic uses • Depression (second choice drug, or as an adjunct with other therapies) • Attention deficit hyperactivity disorder (second choice drug). • Smoking cessation (20-25% of success)

13. Heterocyclic (atypical) AntidepressantMIRTAZAPINE Mechanism of action • Blockade of presynaptic alpha-2 receptors, which results in increased release of norepinephrine from noradrenergic nerve endings, and of serotonin from serotonergic nerve endings. • Blockade of 5-HT2A/C presynaptic receptors. • (It is not known which one of those two actions is more important for the antidepressanteffect) • Blockade of H1 receptors (which likely mediates the sedative effects) Adverse effects • Sedation and drowsiness (up to 40%), dizziness. • Constipation (10%), appetite stimulation, weight gain (up to 15%) Therapeuticuses • Depression (second choice drug, but sometimes highly effective)

14. Adverse Effects of Antidepressants All antidepressants increase the risk for suicide in patients 25 and under. Since failure to start treatment is also a risk for suicide, pharmacological and cognitive behavioral therapy are recommended with close supervision.

15. Adverse effects oftricyclic antidepressants CNS effects • Drowsiness (the most common CNS effect), sedation, lassitude, fatigue, dysphoria, dizziness • Tremor, paresthesias, seizures (tricyclics lower the seizure threshold) • Pseudoparkinsonism(rare) Autonomic effects • Anticholinergic effects (memory impairment, xerostomia, blurred vision, constipation, urinary retention) Cardiovascular effects • Postural hypotension • Cardiac arrhythmias, due to antimuscarinic and quinidine-like actions [patients with long Q-T intervals are at greater risk] • Cardiomyopathy (after long-term use).

16. Adverse effects of tricyclic antidepressants Other adverse effects • Weight gain (mainly with paroxetine). The mechanism isunknown • Sexual dysfunction • SIADH secretion (rare) Overdosage • Tricyclics have a narrow therapeutic index. Manifestations include agitation, delirium, hyperpyrexia, convusions, coma, cardiac arrhythmias, circulatory collapse

17. Adverse effects of MAO inhibitors • Postural hypotension (common), edema. • Headache, insomnia, nightmares, nervousness. • Switch into mania ( about 10% of patients with bipolar disorders) • Weight gain • Sexual dysfunction (the highest rates of all the antidepressants). • Dangerous interactions with certain foods and with serotonergic drugs. • Hypertensive crisis (see interactions below); is rare but can be lethal.

18. Adverse effects of SSRIs and SNRIs GI effects • Anorexia, nausea and vomiting (these are the most common reason for discontinuation, but usually dissipated in a week), • Diarrhea (up to 20%) (due to increased serotonergic activity in the gut) CNS effects • Sexual dysfunction (up to 50%) • Sleep disturbances (up to 30%) (insomnia, more vivid and memorable dreams, morningsleepiness). • Seizures (in patients at risk) • Extrapyramidal symptoms (tremor, akathisia, dystonias) (rare) (serotonin and dopamine appear to have an inverse relationship in certain areas of the brain, whereby central stimulation of 5-HT receptors result in inhibition of dopaminergic transmission).

19. Adverse effects of SSRIs and SNRIs Other adverse effects • Weight gain (mechanism unknown) • SIADH (rare) • Serotoninsyndrome(seebelow) • SSRI (mainly fluoxetine and paroxetine) are inhibitors of the cytochrome P450 system and therefore can increase the effects of several drugs given concomitantly (see interactions below). • Discontinuation syndrome (abrupt discontinuation of an SSRI or SNRI can cause a variety of symptoms that can be quite distressing. These include dizziness, nausea and vomiting, flulike symptoms, irritability and anxiety.)

20. Antidepressant induced Sexual Dysfunction Incidence • Overall frequency 30-50%. • Incidence seems the highest with SSRIs/SNRIs (mainly paroxetine and fluoxetine) and the lowest with bupropion and mirtazapine. Pathophysiology • Serotonin is mainly an inhibitory neurotransmitter in the CNS • Serotonergic pathways from the raphe nuclei project upward and inhibit the mesolimbic dopamine system. This inhibition likely mediates the decreased libido anorgasmia. • Serotonergic pathways from the raphe nuclei project downward to the spinal cord and likely inhibit the mechanistic aspects of sexual function (erection, ejaculation, vaginallubrication, clitoralcongestion) Symptoms and signs • In males: erectile dysfunction, priapism, delayed ejaculation • In females: decreased vaginal lubrication and clitoral congestion. • In both sexes: decreased libido, partial or complete anorgasmia Therapy • Reduction to minimal effective dose (often difficult to find) • Changingantidepressant • Adding drugs which improve sexual function (sildenafil, dextroamphetamine, methylphenidate, amantadine, etc)

21. The Serotonin Syndrome Etiology A large number of medications either alone or in combination can produce the serotonin syndrome, when given in high doses. These include antidepressants, opioids, psychostimulants, triptans, psychedelics, herbs (St. John’s wort, ginseng, nutmeg). The combination of two drugs that enhance serotonin transmission (i.e. SSRIs/SNRIs with MAO inhibitors or with tricyclics antidepressants) can be particularly dangerous. Pathophysiology Overstimulation of 5-HT1A receptors (and perhaps of 5-HT2 receptors) appears to contribute substantially to the condition.

22. The Serotonin Syndrome Clinical course and prognosis • Upon discontinuation of the offending drug most cases resolve within 24 hours, but the syndrome can be fatal (likely because of malignant hyperthermia). Therapy • For mild cases: discontinuation of the offending drug. • For more serious cases: • Benzodiazepines for agitation and somatic effects. • Serotonin antagonists (cyproheptadine) or atypical neuroleptics with serotoninblockingactivity (likeolanzapine). • Beta-blockers for tachycardia and autonomic instability. • Dantrolenefor hyperthermia.

23. Contraindications and Precautions of Antidepressants Tricyclicsandheterocyclics • Seizure disorders, Parkinson’s disease • Suicidal ideation • Cardiac disease ( Long Q-T intervals, arrhythmias, myocardial infarction, etc.) • Glaucoma • Gastroesophagealreflux disease, hiatal hernia • Prostatic hypertrophy • Pregnancy (tricyclics are included in FDA pregnancy risk category D) • Children • Elderly (antimuscarinic effects may be greatly enhanced)

24. Contraindications and Precautions of Antidepressants SSRIs, SNRIs • Seizuredisorders • Suicidal ideation • Hepatic disease (liver clearance can be decreased) • Anorexia (SSRIs can decrease hunger) • Sleepdisturbances • Concurrent therapy with other antidepressants, benzodiazepines, betablockers, methadone, etc. • Children (about 1 out of 50 children become more suicidal) • Pregnancy (only paroxetine is classified in FDA pregnancy risk category D)

25. Therapeutic Uses of Antidepressants • Most antidepressants are of equivalent efficacy in patients with major depressive disorder, when administered in comparable doses. • Therefore many clinicians select an antidepressant by matching the patient’s presenting symptoms to the adverse effect profile of antidepressantmedications. • When one antidepressant is ineffective the addition of another antidepressant can be useful (so called augmentation therapy) • Drugs used effectively in augmentation therapy include lithium, bupropion, buspirone, lamotigrine and triiodothyronine. • A maintenance therapy with an antidepressant should be maintained for least 9-12 months. • Approximately 65-70% of patients with varying types of depression improve with drug therapy compared with 30-40% who improve with placebo.