Drugs for Depressive Disorders Kaukab Azim, MBBS, PhD

Drug List Antidepressants Tricyclics Atypicals MAO inhibitors SSRIs SNRIs Non Selective Selective Imipramine Amitriptamine Clomipramine Trazodone Bupropion Mirtazapine Phenelzine Selegiline* Fluoxetine Paroxetine Sertraline Citalopram Venlafaxine * This drug will be covered in another lecture

Classification of Depressive Disorders (from DSM IV text revision) Type Features Major depressive disorder (endogenous depression – about 20% of all depressions) Depression is autonomous and is unresponsive to changes in life. Biological factors seem important (family history). It can occur as a single episode or may be recurrent. Dysthymic disorder A mood disorder with chronic (long-term) depressive symptoms that are present most of the day, more days than not, for a period of at least two years Depressive disorder not otherwise specified Any depressive disorder that does not meet the criteria of a specific disorder. Examples are Minor depressive disorder Recurrent brief depressive disorder

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. Monoamine oxidase inhibitors Non selective inhibition of both MAO A and MAO B (Phenelzine). Selective inhibition of MAO B. (Selegiline).

3.Atypical ( also called heterocyclic) antidepressants (HEADS) Mechanisms are often unclear but in most cases the final result is an effect on monoamines or monoamine receptors. 4.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) 5.Selective serotonin & norepinephrine reuptake inhibitors (SNRIs) Blockade of the reuptake of 5-HT and NE.

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(Brain derived neurotrophic factor) which increases neurogenesis, mainly in the hippocampus.

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. 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, transdermal patch (selegiline).

Tricyclics SSRIs SNRIs Heterocyclics Reuptake and Blocking Activity and Receptor Blocking Activity of Antidepressants Drug Amine pump block Receptor Block 5-HT NE DA 5-HT2 Alpha-1 M H1 Tricyclics Imipramine ++ + 0/+ Amitriptyline +++ Clomipramine Heterocyclics Trazodone Bupropion Mirtazapine Alpha2 SSRIs Fluoxetine Paroxetine Citalopram SNRIs Venlafaxine

Heterocyclic (atypical) Antidepressant TRAZODONE 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(A persistent painful erection), 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.

Heterocyclic (atypical) Antidepressant BUPROPION 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-dependent effect). 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)

Heterocyclic (atypical) Antidepressant MIRTAZAPINE 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 antidepressant effect) 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%) Therapeutic uses Depression (second choice drug, but sometimes highly effective)

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.

Adverse effects of tricyclic antidepressants CNS effects Drowsiness (the most common CNS effect), sedation, lassitude(Heaviness), 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).

Adverse effects of tricyclic antidepressants Other adverse effects Weight gain (mainly with paroxetine). The mechanism is unknown Sexual dysfunction SIADH(Syndrome of inapropriate anti-diuretic hormone) secretion (rare) Over dosage Tricyclics have a narrow therapeutic index. Manifestations include agitation, delirium, hyperpyrexia, convulsions, coma, cardiac arrhythmias, circulatory collapse

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 is rare but can be lethal.

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, morning sleepiness). Seizures (in patients at risk) Extrapyramidal symptoms (tremor, akathisia(Involuntary movements), dystonias) (rare).

Adverse effects of SSRIs and SNRIs Other adverse effects Weight gain (mechanism unknown) SIADH (rare) Serotonin syndrome SSRI (mainly fluoxetine and paroxetine) are inhibitors of the cytochrome P450 system and therefore can increase the effects of several drugs given concomitantly. 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.)

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 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(Excitement) Therapy Reduction to minimal effective dose (often difficult to find) Changing antidepressant Adding drugs which improve sexual function (sildenafil, dextroamphetamine, methylphenidate, amantadine, etc)

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 serotonin blocking activity (like olanzapine). Beta-blockers for tachycardia and autonomic instability. Dantrolene for hyperthermia.

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

Contraindications and Precautions of Antidepressants SSRIs, SNRIs Seizure disorders Suicidal ideation Hepatic disease (liver clearance can be decreased) Anorexia (SSRIs can decrease hunger) Sleep disturbances 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)

Therapeutic Uses of Antidepressants Most antidepressants are of equivalent efficacy in patients with major depressive disorder, when administered in comparable dose. 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.