PHARMACOTHERAPY - I PHCY 310 University of Nizwa College of Pharmacy and Nursing School of Pharmacy PHARMACOTHERAPY - I PHCY 310 Lecture -11 Psychiatric Disorders “Depression” Dr. Sabin Thomas, M. Pharm. Ph. D. Assistant Professor in Pharmacy Practice School of Pharmacy University of Nizwa

Course Outcome Upon completion of this lecture the students will be able to Explain depression based on DCM-IV criteria, Describe pathophysiology, non-pharmacological and pharmacological treatment for depression, Individualize the treatments for depressive patients.

Depression is a mental disorder characterized by low mood, and by loss of interest or pleasure in normally enjoyable activities.

PATHOPHYSIOLOGY Biogenic amine hypothesis. Depression may be caused by decreased brain levels of the neurotransmitters norepinephrine (NE), serotonin (5-HT), and dopamine (DA). Postsynaptic changes in receptor sensitivity. Changes in sensitivity of NE or 5-HT2 receptors may relate to onset of depression.

CLINICAL PRESENTATION Emotional symptoms: diminished ability to experience pleasure, loss of interest in usual activities, sadness, pessimistic outlook, crying spells, hopelessness, anxiety (present in almost 90% of depressed outpatients), feelings of guilt, and psychotic features (e.g., auditory hallucinations, delusions). Physical symptoms: fatigue, pain (especially headache), sleep disturbance, appetite disturbance (decreased or increased), loss of sexual interest, and GI and cardiovascular complaints (especially palpitations). Intellectual or cognitive symptoms: decreased ability to concentrate or slowed thinking, poor memory for recent events, confusion, and indecisiveness.

NONPHARMACOLOGIC TREATMENT Psychotherapy alone is not recommended for the acute treatment. Cognitive therapy, behavioral therapy, and interpersonal psychotherapy appear to be equal in efficacy. Electroconvulsive therapy (ECT) is a safe and effective treatment for major depressive disorder. Bright light therapy (i.e., the patient looking into a 10,000-lux intensity light box for about 30 min/day) may be used for patients with seasonal affective disorder

PHARMACOLOGIC THERAPY—GENERAL THERAPEUTIC PRINCIPLES Factors that influence the choice of antidepressant include patient’s history of response, history of familial response, concurrent medical conditions, presenting symptoms, potential for drug–drug interactions, comparative side-effect profiles of various drugs, patient preference, and drug cost. The acute phase of treatment lasts 6 to 10 weeks, and the goal is remission (i.e., absence of symptoms). The continuation phase lasts 4 to 9 months after remission. The goal is to eliminate residual symptoms or prevent relapse. The maintenance phase lasts at least 12 to 36 months, and the goal is to prevent recurrence of a separate episode of depression.

Therapeutic Choices Pharmacologic Choices 1) Selective Serotonin Reuptake Inhibitors (SSRIs) SSRIs are the first-choice antidepressants due to greater tolerability and ease of dosing. Escitalopram, the stereoisomer of citalopram, has a similar side effect profile but superior efficacy to citalopram. Paroxetine produces more extrapyramidal-type adverse effects than other SSRIs. Fluoxetine has the longest half life as well as its active metabolite, desmethylflouxetine. So they have the advantage of reduced risk of discontinuation syndrome. Sertraline doses shouldn’t exceed 150 mg/day for longer than 8 weeks to avoid overdose tachycardia.

2) Dual Action Antidepressants Bupropion, a norepinephrine and dopamine reuptake inhibitor, that is also considered a first-line agent for depression, and is also indicated for smoking cessation. Bupropion is usually initiated at 100 mg twice daily, and this dose may be increased to 100 mg three times daily after 3 days. Trazodone is a (5HT2) receptor antagonist with weak serotonin reuptake inhibitory effects. Trazodone causes severe hypotension and sedation due to blocking of α receptors, and H1 receptors respectively. So, it is prescribed at low doses (50–100 mg) as a hypnotic in combination with other antidepressants.

Mirtazapine (NaSSA) is also associated with sedation in addition to the problem of weight gain. Venlafaxine (SNRI) requires cardiac monitoring because of cardiovascular toxicity (e.g. hypertension, tachycardia). Duloxetine, another SNRI that has comparable efficacy to venlafaxine. Duloxetine is also indicated for neuropathic pain and for pain associated with fibromyalgia. 3) Tricyclic Antidepressants (TCAs) TCAs are second–line antidepressants due to tolerability and safety concerns, especially cardiotoxicity following overdose. Nortriptyline, a metabolite of amitriptyline, has been used to treat depression in elderly patients. Clomipramine, the most serotonergic TCA, is favoured in the treatment of obsessive compulsive disorder.

The usual initial adult dose of most TCAs is 50 mg at bedtime, and the dose may be increased by 25 to 50 mg every third day Monoamine Oxidase Inhibitors (MAOIs) Use of the irreversible (MAOIs) phenelzine and tranylcypromine carries the risk of fatal food and drug interactions (serotonin syndrome, hypertensive crisis). Moclobemide is a reversible and selective MAO-A inhibitor that does not require the same dietary restrictions as irreversible MAOIs. Moclobemide acts as an alternative 1st line antidepressant to SSRI or SNRI agents, while irreversible MAOIs are 3rd line agents for treating depression.

Other treatments: 1. Non-drug therapy: psychotherapy such as cognitive behavior therapy (CBT) is used in combination with antidepressants for severe major depression. psychotherapy is the 1st line therapy of mild to moderate depression. 2. St John’s wort (Hypericum perforatum): they can only be used in the short term management of mild to moderate, but not severe depression. 3. Electroconvulsive therapy (ECT): although safe and with a rapid antidepressant response, ECT is short lived and always requires an antidepressant to prevent relapse.

ADVERSE EFFECTS Tricyclic Antidepressants and Other Heterocyclics Anticholinergic side effects (e.g., dry mouth, blurred vision, constipation, urinary retention, tachycardia, memory impairment, and delirium) and sedation are more likely to occur with the tertiary amine TCAs. Orthostatic hypotension and resultant syncope, a common and potentially serious adverse effect of the TCAs, Other side effects that may lead to noncompliance include weight gain and sexual dysfunction. Abrupt withdrawal of TCAs (especially high doses) may result in symptoms of cholinergic rebound (e.g., dizziness, nausea, diarrhea, insomnia, restlessness).

Selective Serotonin Reuptake Inhibitors The SSRIs produce fewer sedative, anticholinergic, and cardiovascular adverse effects than the TCAs and are less likely to cause weight gain than the TCAs. The primary adverse effects include nausea, vomiting, diarrhea, headache, insomnia, fatigue, and sexual dysfunction. Drug Interactions Increased plasma concentrations of TCAs and symptoms of toxicity may occur when fluoxetine and paroxetine are added to a TCA regimen.

Special Population Elderly Patients The SSRIs are often selected as first-choice antidepressants in elderly patients. Bupropion and venlafaxine may also be chosen because of their milder anticholinergic and less frequent cardiovascular side effects. Elderly patients should receive one-half the initial dose given to younger adults, and the dose is increased at a slower rate. The elderly may require 6 to 12 weeks of treatment to achieve the desired antidepressant response. Children and Adolescents Symptoms of depression in childhood include boredom, anxiety, failing adjustment, and sleep disturbance. The FDA has established a link between antidepressant use and suicidality (suicidal thinking and behaviors) in children, adolescents, and young adults 18 to 24 years old.

All antidepressants carry a black box warning providing cautions in the use of all antidepressants in this population Pregnancy As a general rule, if effective, nondrug approaches are preferred when treating depressed pregnant patients. No major teratogenic effects have been identified with the SSRIs or TCAs. However, evaluations to date suggest a possible association of fluoxetine with low birth weight and respiratory distress. Dosing A 6-week antidepressant trial at a maximum dosage is considered an adequate trial. Patients must be told about the expected lag time of 2 to 4 weeks before the onset of antidepressant effect. To prevent relapse, antidepressants should be continued at full therapeutic doses for 4 to 9 months after remission.