Medical Pharmacology Topics   

Mood Disorders

Mood disorders may be classified as primary (not arising from other conditions) or secondary (due to endocrine or other medical problems). Primary disorders may be unipolar, i.e. depression or dysthymia, or bipolar (type I or type II). Unipolar disorders are more common in females. Dysthymia is a more chronic, lower level depressive state than mayor depression. Bipolar disorders have a stronger genetic predisposition than unipolar. Type I bipolar disorder involves severe manic episodes, and is as common in males as in females. Type II bipolar disorder involves mild manic episodes, and is most common in females.

Mood disorders involve some level of genetic predisposition and/or environmental influences, yielding complex CNS changes. Several neurotransmitters seem to be implicated in altered receptor function mainly seratonin and norepinephrine.

There are several types of antidepressants: tricyclic antidepressants (TCAs), heterocyclics, selective seratonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs) and other newer an miscellaneous agents.

The tricyclic antidepressant (TCAs) have a three ring structure and block the reuptake of biogenic amines. Some are more selective to norepinephrine or seratonin. TCAs are generally well absorbed orally, highly bound to plasma proteins (hard to remove by dialysis), and have a t1/2 of 20-60 hrs. They are metabolized by hepatic microsomal enzymes and some have active metabolites that are potent antidepressants, for example:

imipramine desipramine

amitriptyline nortriptyline

TCAs elevate mood after 2-6 weeks of use. Some are sedative (amitriptyline, doxepin) while others are stimulating (desipramine). They improve sleep by increasing stage 4 sleep and REM latency and by decreasing total REM sleep. They are used to treat depression, panic disorders, obsessive-compulsive disorders (chlomipramine) and other non- mood disorders like chronic pain, attention deficit disorder, enuresis and fibromyalgia/chronic fatigue.

Side effects of TCAs may be autonomic or cardiovascular: antimuscarinic symptoms (blurred vision, dry mouth, sexual dysfunction), alpha 1-blockade, sinus tachycardia, postural hypotension, prolonged QT and PR intervals, etc. Weight gain may also occur. The cardiovascular effects are especially dangerous if TCAs are used in an overdose while attempting suicide. Overdose signs are similar to atropine poisoning: dilated pupils, dry skin/mucosa, initial excitement, seizures, arrhythmias, and coma. Treatment includes gastric lavage with activated charcoal, monitoring and treatment of arrhythmias, fluids and other supportive efforts.

The selective seratonin reuptake inhibitors (SSRIs) are as effective as the TCAs but have much fewer side effects and are relatively safe if taken as an overdose. Currently several are available: fluoxetine (Prozac™), sertraline (Zoloft™), parxentine (Paxil™), fluoxamine and citalopram. Fluoxetine is the prototype agent. It is well absorbed orally and has a t1/2 of 24-48 hrs. It has an active metabolite wit ha t1/2 of several days.

Since fluoxetine does not have much affinity for other peripheral receptors, it does not have the side effects of TCAs. Adverse effects include nausea, upset GI (acts on gut 5-HT receptors), insomnia, agitation and delayed or difficult orgasm/ejaculation or premature ejaculation SSRIs are inhibitors of different enzyme systems, so if other drugs are given their levels must be monitored.

Monoamine oxidase (MAO) is a mitochondrial enzyme that breaks down biogenic amines. There are two types of MAO: A and B. A MAO-A inhibitor would be more beneficial in the treatment of depression, while a MAO-B inhibitor would be more beneficial for Parkinson's disease. All currently available MAO inhibitors (MAOIs) are irreversible blockers of both MAO-A and MAO-B. Seratonin is the preferred substrate for MAO-A, and clorgiline is an experimental selective blocker. Phenyethylamine is the preferred substrate for MAO-B, and deprenyl is an experimental selective blocker.

All MAOIs are well absorbed. Maximal enzyme inhibition is reached in 5-10 days and lasts 2-3 weeks after discontinuing intake due to irreversible blockade. The main pharmacologic effects of MAOIs are elevated mood, REM sleep suppression and CNS stimulation. Side effects include postural hypotension, insomnia and hepatotoxicity. A diet low in tyramine should be followed while on a MAOI to avoid hypertensive crisis.

Drugs used in the treatment of bipolar disorders include lithium salts (usually Li2CO3) carbamazepine and valproic acid (divalproate sodium). Lithium salts are rapidly absorbed and widely distributed, and are mostly excreted by the kidneys. They have a narrow therapeutic index (0.6 - 1.4 mEq/L). Adverse effects include GI disturbances, tremors, hypothyroidism (competes with iodine) and renal toxicity (with chronic use). Regular monitoring of renal and thyroid function is needed. Toxic levels are treated with fluids, diuresis and dialysis.

Divalproate sodium and carbamazapine are antiepileptic drugs also approved for the treatment of bipolar disorder. Plasma levels of divalproate must be monitored to maintain therapeutic levels. Adverse effects of include sedation, weight gain and hepatic toxicity.

Recently, the atypical antipsychotics are being used to treat bipolar mania. Olazapine has been approved for this use. They may have the advantage of a more rapid onset of action, i.e. rapid stabilizing effect.

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