Clinical pharmacology of antidepressants

Clinical pharmacology of antidepressants
Domina Petric, MD

Katzung, Masters, Trevor. Basic and clinical pharmacology.
Clinical indications Katzung, Masters, Trevor. Basic and clinical pharmacology.

Depression Most antidepressants are approved for both acute and long-term treatment of major depression. Acute episodes of major depressive disorder (MDD) tend to last about 6-14 months untreated, but at least 20% of episodes last 2 years or longer. The goal of acute treatment of MDD is remission of all symptoms. Katzung, Masters, Trevor. Basic and clinical pharmacology.

Depression Antidepressants may not achieve their maximum benefit for 1-2 months or longer. It is not unusual for a trial of therapy to last 8-12 weeks at therapeutic doses. The antidepressants are successful in achieving remission in about 30-40% of patients within a single trial of 8-12 weeks. If an inadequate response is obtained, therapy is often switched to another agent or augmented by addition of another drug. Katzung, Masters, Trevor. Basic and clinical pharmacology.

Depression Bupropion or mirtazapine might be added to an SSRI or SNRI to augment antidepressant benefit if monotherapy is unsuccessful. 70-80% percent of patients are able to achieve remission with sequenced augmentation or switching strategies. Once an adequate response is achieved, continuation therapy is recommended for a minimum of 6-12 months to reduce the substantial risk of relapse. Katzung, Masters, Trevor. Basic and clinical pharmacology.

Depression 85% of patients who have a single episode of MDD will have at least one recurrence in a lifetime. Many patients have multiple recurrences. These recurrences may progress to more serious, chronic and treatment-resistant episodes. It is not unusual for patients to require maintenance treatment to prevent recurrences. Katzung, Masters, Trevor. Basic and clinical pharmacology.

Depression It is commonly recommended that patients be considered for long-term maintenance treatment if they have had two or more serious MDD episodes in the previous 5 years or 3 or more serious episodes in a lifetime. Patients with bipolar depression may not benefit much from antidepressants even when added to mood stabilizers. Antidepressants are sometimes associated with switches into mania or more rapid cycling. Katzung, Masters, Trevor. Basic and clinical pharmacology.

Depression Psychotherapeutic interventions (cognitive behavior therapy) appear to be as effective as antidepressant treatment for mild to moderate forms of depression. Psychotherapy is often combined with antidepressant treatment. The combination is more effective than either strategy alone. Katzung, Masters, Trevor. Basic and clinical pharmacology.

Anxiety disorders A number of SSRIs and SNRIs have been approved for all the major anxiety disorders: PTSD (post-traumatic stress disorder) OCD (obsessive compulsive disorder) social anxiety disorder (SAD) GAD (generalised anxiety disorder) panic disorder Katzung, Masters, Trevor. Basic and clinical pharmacology.

Anxiety disorders Panic disorder is characterized by recurrent episodes of brief overwhelming anxiety, which often occur without precipitant. Patients may begin to fear having an attack or they avoid situations in which they might have an attack. Katzung, Masters, Trevor. Basic and clinical pharmacology.

Anxiety disorders GAD is characterized by a chronic, free-floating anxiety and undue worry that tends to be chronic in nature. Katzung, Masters, Trevor. Basic and clinical pharmacology.

Anxiety disorders The benzodiazepines provide much more rapid relief of both generalised anxiety and panic than do any of the antidepressants. The antidepressants are more effective in the long-term treatment of these anxiety disorders. Antidepressants do not carry the risks of dependence and tolerance that may occur with benzodiazepines. Katzung, Masters, Trevor. Basic and clinical pharmacology.

Anxiety disorders OCD is characterized by repetitive anxiety-provoking thoughts (obsessions) or repetitive behaviors aimed at reducing anxiety (compulsions). Clomipramine and several of the SSRIs are approved for the treatment of OCD. These drugs are moderately effective. Behavior therapy is usually combined with the antidepressant for additional benefits. Katzung, Masters, Trevor. Basic and clinical pharmacology.

Anxiety disorders Social anxiety disorder: patient experiences severe anxiety in social interactions. This anxiety may limit patients´ ability to function adequately in their jobs or interpersonal relationships. Several SSRIs and venlafaxine are approved for the treatment of social anxiety. Katzung, Masters, Trevor. Basic and clinical pharmacology.

Anxiety disorders PTSD is manifested when a traumatic or life-threatening event results in intrusive anxiety-provoking thoughts or imagery, hypervigilance, nightmares and avoidance of situations that remind the patient of the trauma. SSRIs are considered first-line treatment for PTSD and can benefit a number of symptoms including anxious thoughts and hypervigilance. Psychotherapeutic interventions! Katzung, Masters, Trevor. Basic and clinical pharmacology.

Pain disorders Antidepressants possess analgesic properties independent of their mood effects. TCAs are used in the treatment of neuropathic and other pain conditions. Medications that possess both norepinephrine and 5-HT reuptake blocking properties are often useful in treating pain disorders. Ascending corticospinal monoamine pathways are important in the endogenous analgesic system. Katzung, Masters, Trevor. Basic and clinical pharmacology.

Pain disorders Chronic pain conditions are commonly associated with major depression. Duloxetine is approved for the treatment of chronic joint and muscle pain. Milnacipran has been approved for the treatment of fibromyalgia. Katzung, Masters, Trevor. Basic and clinical pharmacology.

Premenstrual dysphoric disorder
5% of women in the child-bearing years will have prominent mood and physical symptoms during the late luteal phase of almost every cycle: anxiety depressed mood irritability insomnia fatigue other physical symptoms Katzung, Masters, Trevor. Basic and clinical pharmacology.

Premenstrual dysphoric disorder
Fluoxetine and sertraline are approved for this indication. Treating for 2 weeks out of the month in the luteal phase may be as effective as continuous treatment. The rapid effects of SSRIs in PMDD may be associated with rapid increases in pregnenolone levels. Katzung, Masters, Trevor. Basic and clinical pharmacology.

Smoking cessation Bupropion is approved for the smoking cessation. This drug may mimic nicotine´s effects on dopamine and norepinephrine. Bupropion may antagonize nicotinic receptors. Nicotine is also known to have antidepressant effects in some people: bupropion may substitute for this effect. Nortriptyline may also be helpful in smoking cessation. Katzung, Masters, Trevor. Basic and clinical pharmacology.

It may be fatal in 10% of cases.
Eating disorders Bulimia Anorexia nervosa Bulimia nervosa is characterized by episodic intake of large amounts of food (binges) followed by ritualistic purging through emesis, the use of laxatives or other methods. Hypokalemia! Anorexia is a disorder in which reduced food intake results in a loss of weight of 15% or more of ideal body weight. The person has a morbid fear of gaining weight and a highly distorted body image. It is often chronic. It may be fatal in 10% of cases. Katzung, Masters, Trevor. Basic and clinical pharmacology.

Eating disorders Antidepressants appear to be helpful in the treatment of bulimia, but not anorexia. Fluoxetine and other antidepressants have shown benefit in reducing the binge-purge cycle. The primary treatment for anorexia is refeeding, family therapy and cognitive behavioral therapy. Bupropion may have some benefits in treating obesity. Katzung, Masters, Trevor. Basic and clinical pharmacology.

Other uses Enuresis in children is sometimes treated with TCAs. Duloxetine is approved for the treatment of urinary stress incontinence. SSRIs may be helpful for treating vasomotor symptoms in perimenopause. SSRIs delay orgasm in some patients: treatment of premature ejaculation. Bupropion: treatment of sexual adverse effects of SSRIs. Katzung, Masters, Trevor. Basic and clinical pharmacology.

Choosing an antidepressant
II. Choosing an antidepressant Katzung, Masters, Trevor. Basic and clinical pharmacology.

Choice of an antidepressant for the treatment of depression:
cost availability adverse effects potential drug interactions patient´s history of response age gender medical status Katzung, Masters, Trevor. Basic and clinical pharmacology.

!!! Older patients are particularly sensitive to the anticholinergic effects of the TCAs. The CYP3A4-inhibitor SSRI fluvoxamine may interact with many other medications that an older patient may require. Female patients may respond to and tolerate serotonergic better than noradrenergic or TCA antidepressants. Katzung, Masters, Trevor. Basic and clinical pharmacology.

!!! Patients with narrow-angle glaucoma may have an exacerbation with noradrenergic antidepressants. Bupriopion and other antidepressants lower the seizure threshold in epilepsy patients. Katzung, Masters, Trevor. Basic and clinical pharmacology.

MDD SSRIs are the most commonly prescribed first-line agents in the treatment of both MDD and anxiety disorders. SNRIs, bupropion and mirtazapine are also reasonable first-line agents for the treatment of MDD. Bupropion, mirtazapine and nefazodone are the antidepressants with the least association with sexual side effects. Katzung, Masters, Trevor. Basic and clinical pharmacology.

Bupropion Mirtazapin The primary indication for bupropion is major depression, including seasonal (winter) depression. Off-label uses of bupropion include the treatment of attention deficit hyperkinetic disorder (ADHD). The primary indication for mirtazapine is major depression. It has strong antihistamine properties so it is occasionaly used as a hypnotic and as an adjunctive treatment to more activating antidepressants. Katzung, Masters, Trevor. Basic and clinical pharmacology.

TCA, MAOI The TCAs and MAOIs are now relegated to second or third line treatment for MDD. Both TCAs and MAOIs are potentially lethal in overdose, require titration to achieve a therapeutic dose, have serious drug interactions and have many troublesome adverse effects. Katzung, Masters, Trevor. Basic and clinical pharmacology.

Other TCAs and SNRIs are useful in the treatment of pain conditions. SSRIs and the highly serotonergic TCA-clomipramine are effective in the treatment of OCD. Bupropion and nortriptyline are useful in the treatment of smoking cessation. Katzung, Masters, Trevor. Basic and clinical pharmacology.

III. Dosing Katzung, Masters, Trevor. Basic and clinical pharmacology.

Usual therapeutic dosage (mg/day)
SSRIs mg/day Citalopram 20-60 Escitalopram 10-30 Fluoxetine Fluvoxamine Paroxetine Sertraline 50-200 Katzung, Masters, Trevor. Basic and clinical pharmacology.

SNRIs mg/day Venlafaxine 75-375 Desvenlafaxine 50-200 Duloxetine 40-120 Milnacipran Katzung, Masters, Trevor. Basic and clinical pharmacology.

Tricyclics mg/day Amitriptyline Clomipramine Desipramine Doxepin Imipramine Nortriptyline 50-150 Protriptyline 15-60 Trimipramine maleate Katzung, Masters, Trevor. Basic and clinical pharmacology.

5-HT2 antagonists mg/day Nefazodone Trazodone Katzung, Masters, Trevor. Basic and clinical pharmacology.

Tetracyclics and unicyclics mg/day Amoxapine Bupropion Maprotiline Mirtazapine 15-45 Katzung, Masters, Trevor. Basic and clinical pharmacology.

MAOIs mg/day Isocarboxazid 30-60 Phenelzine 45-90 Selegiline 20-50 Tranylcypromine Katzung, Masters, Trevor. Basic and clinical pharmacology.

Dosing Patients with MDD, who show little or no benefit after at least 4 weeks of treatment, may benefit from a higher dose. The dose is generally titrated to the maximum dosage recommended or to the highest dosage tolerated. Some patients may benefit from doses lower than the usual minimum recommended therapeutic dose. Katzung, Masters, Trevor. Basic and clinical pharmacology.

Dosing TCAs and MAOIs typically require titration to a therapeutic dosage over several weeks. Dosing of the TCAs may be guided by monitoring TCA serum levels. Some anxiety disorders may require higher doses of antidepressants than are used in the treatment of MDD. Patients with OCD often require maximum or somewhat higher than maximum recommended MDD doses. Katzung, Masters, Trevor. Basic and clinical pharmacology.

Dosing In the treatment of pain disorders, modest doses of TCAs are often sufficient. Imipramine mg/day might be beneficial in the treatment of pain associated with a neuropathy. SNRIs are usually prescribed in pain disorders at the same doses used in the treatment of depression. Katzung, Masters, Trevor. Basic and clinical pharmacology.

IV. Adverse effects Katzung, Masters, Trevor. Basic and clinical pharmacology.

Adverse effects All antidepressants are associated with the risk of increased suicidality in patients under the age 25. Use of antidepressants is associated with suicidal ideation and gestures, but not completed suicides, in up to 4% of patients under 25 years (clinical trials). Katzung, Masters, Trevor. Basic and clinical pharmacology.

SSRIs SSRIs enhance serotonergic tone, not just in the brain, but throughout the body. Increased serotonergic activity in the gut is commonly associated with nausea, gastrointestinal upset, diarrhea and other GI symptoms. GI adverse effects usually emerge early in the course of treatment and tend to improve after the first week. Katzung, Masters, Trevor. Basic and clinical pharmacology.

SSRIs Increasing serotonergic tone at the level of the spinal cord and above is associated with diminished sexual function and interest. At least 30-40% of patients treated with SSRIs report loss of libido, delayed orgasm or diminished arousal. The sexual effects often persist as long as the patient remains on the antidepressant, but may diminish with time. Katzung, Masters, Trevor. Basic and clinical pharmacology.

SSRIs Other serotonergic side effects are headaches, insomnia or hypersomnia. Some patients gain weight while taking SSRIs, particularly paroxetine. Sudden discontinuation of short half-life SSRIs (paroxetine, sertraline) is associated with a discontinuation syndrome: dizziness, paresthesias. These symptoms beginn 1 or 2 days after stopping the drug and persist for 1 week or longer. Katzung, Masters, Trevor. Basic and clinical pharmacology.

SSRIs FDA teratogen classification C category! Paroxetine is D category: cardiac septal defects in first trimester exposures. Katzung, Masters, Trevor. Basic and clinical pharmacology.

SNRIs SNRIs have many of the serotonergic adverse effects associated with SSRIs. These agent may also have noradrenergic effects: increased blood pressure and heart rate, CNS activation (insomnia, anxiety, agitation). A dose-related increase in blood pressure is more common with the immediate-release form of venlafaxine, as well as cardiac toxicity. Duloxetine rarely causes hepatic toxicity in patients with a history of liver damage. Discontinuation syndrome! Katzung, Masters, Trevor. Basic and clinical pharmacology.

TCAs Anticholinergic effects are the most common: dry mouth, constipation, urinary retention, blurred vision and confusion. These effects are more common with tertiary amine TCAs (amitriptyline, imipramine) than with the secondary amine TCAs (desipramine, nortriptyline). Potent α-blocking property: orthostatic hypotension. Katzung, Masters, Trevor. Basic and clinical pharmacology.

TCAs H1 antagonism: weight gain and sedation. Class 1A antiarrhythmic agents: arrhythmogenic at higher doses. Sexual effects, particularly with highly serotonergic TCAs (clomipramine). Prominent discontinuation syndrome: cholinergic rebound and flulike symptoms. Katzung, Masters, Trevor. Basic and clinical pharmacology.

5-HT2 antagonists The most common adverse effects are sedation and gastrointestinal disturbances. Sedative effects, particularly with trazodone, can be very prononuced. The GI effects are dose-related. Sexual effects are uncommon with nefazodone or trazodone treatment. Trazodone may rarely be associated with inducing priapism. Katzung, Masters, Trevor. Basic and clinical pharmacology.

5-HT2 antagonists Nefazodone and trazodone are α-blocking agents: dose-related orthostatic hypotension. Nefazodone has been associated with hepatotoxicity: rare fatalities and cases of fulminant hepatic failure requiring transplantation (1/ to 1/ patient-years of nefazodone treatment). Katzung, Masters, Trevor. Basic and clinical pharmacology.

Tetracyclics, unicyclics
Amoxapine is sometimes associated with parkinsonian syndrome (D2-blocking action). Mirtazapine has significant sedative effect. Maprotiline has a moderately high affinity for NET and may cause TCA-like adverse effects and seizures (rarely). Bupropion is occasionally associated with agitation, insomnia and anorexia. Katzung, Masters, Trevor. Basic and clinical pharmacology.

MAOIs Most common adverse effects are orthostatic hypotension and weight gain. The irreversible nonselective MAOIs are associated with the highest rates of sexual effects of all the antidepressants. Anorgasmia! The amphetamine-like properties of some MAOIs contributes to activation, insomnia nad restlessness. Katzung, Masters, Trevor. Basic and clinical pharmacology.

MAOIs Phenelzine tends to be more sedating than selegiline and tranylcypromine. Confusion: higher doses of MAOIs. MAOIs may cause dangerous interactions with certain foods and serotonergic drugs: MAOIs block metabolism of tyramine and similar ingested amines. Sudden discontinuation syndrome: delirium-like presentation with psychosis, excitement and confusion. Katzung, Masters, Trevor. Basic and clinical pharmacology.

Overdose Suicide attempts are a common and unfortunate consequence of major depression. The lifetime risk of completing suicide in patients previously hospitalized with MDD is up to 15%. Overdose, especially with TCAs, can induce lethal arrhythmias: ventricular tachycardia, fibrillation. TCAs overdose can also cause blood pressure changes and anticholinergic effects: altered mental status and seizures. Katzung, Masters, Trevor. Basic and clinical pharmacology.

Overdose A 1500 mg dose of imipramine or amitriptyline is enough to be lethal in many patients. Toddlers toxicity: 100 mg! Treatment: cardiac monitoring, airway support, gastric lavage. Sodium bicarbonate to uncouple the TCA from cardiac sodium channels! Katzung, Masters, Trevor. Basic and clinical pharmacology.

Overdose Overdose with MAOIs: autonomic instability, hyperadrenergic symptoms, psychotic symptoms, confusion, delirium, fever and seizures. Management: cardiac monitoring, vital signs support and lavage. Katzung, Masters, Trevor. Basic and clinical pharmacology.

Overdose Fatalities with SSRIs overdose alone are extremely uncommon. Venlafaxine (SNRI) has been associated with some cardiac toxicity in overdose. Bupropion overdose: seizures. Mirtazapine overdose: sedation, disorientation and tachycardia. Fatal overdose: newer antidepressants with other antidepressant, including alcohol. Treatment: emptying of gastric contents, vital sign support, initial intervention. Katzung, Masters, Trevor. Basic and clinical pharmacology.

Drug interactions Katzung, Masters, Trevor. Basic and clinical pharmacology.

SSRIs The most common are PHARMACOKINETIC interactions. Paroxetine and fluoxetine are potent CYP2D6 inhibitors: administration with TCAs can lead to dramatic and sometimes unpredictable elevations in the tricyclic drug concentration. Fluvoxamine is CYP3A4 inhibitor: elevation of level of diltiazem (bradycardia, hypotension). Citalopram and escitalopram are relatively free of pharmacokinetic interactions. Katzung, Masters, Trevor. Basic and clinical pharmacology.

SSRIs The most serious PHARMACODYNAMIC interaction: SSRIs and MAOIs, which may lead to serotonin syndrome! Katzung, Masters, Trevor. Basic and clinical pharmacology.

SNRIs Venlafaxine is a substrate of CYP2D6. Desvenlafaxine is a minor substrate for CYP3A4. Duloxetine is a moderate inhibitor of CYP2D6: elevation of TCA levels. SNRIs are contraindicated in combination with MAOIs. Katzung, Masters, Trevor. Basic and clinical pharmacology.

TCAs Elevations of TCA levels may occur when combined with CYP2D6 or from constitutional factors (CYP2D6 polymorphism associated with slow metabolism of TCAs and other 2D6 substances). Additive TCA anticholinergic or antihistamine effects with benztropine, diphenhydramine and similar agents. Antihypertensive drugs may exacerbate the orthostatic hypotension induced by TCA. Katzung, Masters, Trevor. Basic and clinical pharmacology.

5-HT2 antagonists Nefazodone is an inhibitor of the CYP3A4 isoenzyme: elevation of triazolam levels, simvastatin levels… Trazodone is a substrate of CYP3A4: ritonavir and ketoconazole (potent inhibitors of CYP3A4) increase trazodone levels. Katzung, Masters, Trevor. Basic and clinical pharmacology.

Bupropion is metabolized primarily by CYP2B6: cyclophosphamide may alter its metabolism. Hydroxybupropion (bupropion metabolite) is a moderate inhibitor of CYP2D6: increase of desipramine levels. Bupriopion should be avoided in patients taking MAOIs. Katzung, Masters, Trevor. Basic and clinical pharmacology.

Mirtazapine is a substrate for several CYP450 enzymes: 2D6, 3A4 and 1A2. Drugs that inhibit these isoenzymes may raise mirtazapine levels. The sedating effects of mirtazapine may be additive with those of CNS depressants (alcohol, benzodiazepines). Katzung, Masters, Trevor. Basic and clinical pharmacology.

Amoxapine and meprotiline are CYP2D6 substrates: they should be used with caution in combination with inhibitors (fluoxetine). These drugs have anticholinergic and antihistaminic properties: additive effects with drugs of similar profile. Katzung, Masters, Trevor. Basic and clinical pharmacology.

MAOIs Pharmacodynamic interaction of MAOIs with serotonergic agents (SSRIs, SNRIs, most TCAs, analgesic agent meperidine) may result in a life-threatening SEROTONIN SYNDROME. The serotonin syndrome is probably caused by overstimulation of 5-HT receptors in the central gray nuclei and the medulla. Symptoms range from mild to lethal. Katzung, Masters, Trevor. Basic and clinical pharmacology.

MAOIs Serotonin syndrome TRIAD: COGNITIVE EFFECTS-delirium, coma AUTONOMIC EFFECTS-hypertension, tachycardia, diaphoresis SOMATIC EFFECTS-myoclonus, hyperreflexia, tremor Katzung, Masters, Trevor. Basic and clinical pharmacology.

MAOIs Most serotonergic antidepressants should be discontinued at least 2 weeks before starting an MAOI. Fluoxetine (long half-life) should be discontinued for 4-5 weeks before and MAOI is initiated. MAOI must be discontinued for at least 2 weeks before starting a serotonergic agent. Katzung, Masters, Trevor. Basic and clinical pharmacology.

MAOIs MAOI combined with tyramine in the diet or with sympathomimetic substrates of MAO is important interaction. MAOI prevents the breakdown of tyramine in the gut: high serum levels of tyramine enhance peripheral noradrenergic effects, including raising blood pressure dramatically. Patients on an MAOI, who ingest large amounts of dietary tyramine, may experience malignant hypertension leading to stroke or myocardial infarction. Katzung, Masters, Trevor. Basic and clinical pharmacology.

MAOIs Patients taking MAOIs require a low-tyramine diet. They should avoid AGED CHEESES, TAP BEER, SOY PRODUCTS AND DRIED SAUSAGES. Similar sympathomimetics may also cause significant hypertension when combined with MAOIs. OTC drugs that contain psudoephedrine (decongestants) and phenylpropanolamine are contraindicated in patients taking MAOIs. Katzung, Masters, Trevor. Basic and clinical pharmacology.

Literature Katzung, Masters, Trevor. Basic and clinical pharmacology. Katzung, Masters, Trevor. Basic and clinical pharmacology.

Clinical pharmacology of antidepressants

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