Antidepressants

Perhaps no other area of pharmacology has experienced the rapid development that has occurred in psychopharmacology during the past two decades. An almost bewildering array of specific and effective psychotropic agents are currently available, with new medications appearing with great frequency. This chapter presents an overview of the major classes of psychopharmacologic drugs to provide the reader with a pragmatic understanding of these potent medications. The most clinically meaningful classification schema is based upon the therapeutic use in patients, as follows: antidepressant medications, lithium and other mood stabilizing medications, anxiolytic or antianxiety medications, and antipsychotic or neuroleptic medications.

The successful search for new and better antidepressant medications has resulted in the two generations of antidepressants that are currently available. The first-generation antidepressants include the tricyclic (TCA) and the monoamine oxidase (MAO) inhibitor antidepressants. To date, no newly developed drug has greater efficacy than the antidepressants in these benefited from tricyclic antidepressants and MAO inhibitors. Other groups of borderline patients in whom mood dysregulation and impulsiveness are prominent have responded to lithium. Still others with explosive outbursts have benefited from carbamazepine. A few such patients have had EEG abnormalities suggestive of epileptic foci in limbic structures. Both borderline and schizotypal patients undergoing cognitive disorganization can improve with low doses of neuroleptic drugs.

Persons with compulsive personality disorder who have obsessional ruminations may benefit from the tricyclic clomipramine (unavailable in the United States). Clomipramine may have specific antiruminative effects which go beyond its antidepressive activity. The utility of other antidepressants for this disorder has not been established, although the MAO inhibitors show promise in compulsives who also experience anxiety or panic attacks.

Methylphenidate may improve inattention and reduce motor overactivity, affective lability, and impulsivity in persons whose personality difficulties are related to adult attention deficit disorder.

The MAO inhibitors are clinically effective and recently have experienced a resurgence in clinical use, but the problems of drug-drug and drug-food interactions have made these the second-line medications in the treatment of depressive disorders. In contrast, the TCAs imipramine and amitriptyline have emerged as the standards for antidepressant efficacy.

No antidepressant is ideal, and all currently available drugs have at least one of the following undesirable characteristics: delayed onset of therapeutic action (7 to 28 days), significant anticholinergic side effects, sedation, cardiotoxicity, weight gain, the possible induction of manic episodes in patients with bipolar disorders, or other equally problematic side effects. Therefore, the developmental goal of the second-generation antidepressants has been to increase efficacy and eliminate side effects, but the search has not met with notable success.

Mechanisms of action

The primary brain mechanism originally hypothesized for the TCA antidepressants was the capacity to increase synaptic concentrations of central nervous system (CNS) monoamin-ergic neurotransmitter substances (e.g., norepinephrine, serotonin, and dopamine) by blocking their reuptake by presynaptic monoamin-ergic neurons. While this is still valid, the focus now is on the regulation of postsynaptic receptor activity in monoaminergic neurons, and down-regulation of neurotransmitter receptors has been identified with the antidepressant effect. Most of the proven antidepressants fit the mechanisms hypothesized, but some newer antidepressants do not. At present, therefore, there is a great deal of information available about how antidepressants may ameliorate the pathophysiologic mechanisms of depressive disorders, but no precise central mechanism^) has been identified by which all drugs with antidepressant properties work.

Clinical conditions in which antidepressant medications are used Antidepressants are very effective in treatment of major depression but do not affect the vicissitudes of mood inherent in normal human behavior nor do they make unhappy people into happy ones. Chronic low-grade depression or dysthymic disorders (neurotic depression) do not respond well to antidepressants, but patients with major depression are very likely to respond. Antidepressants are not often prescribed for patients who become temporarily depressed over difficult and stressful life situations (situational depression).

There is, however, growing evidence that antidepressants are effective in the treatment of some anxiety disorders. TCA and thй MAO inhibitor antidepressants are the drugs of choice for agoraphobia, simple phobias, and panic disorder. Patients with phobic or panic disorders have concomitant anxiety about the recurrence of these attacks; this “anticipatory” anxiety may not respond to antidepressants but often requires treatment with antianxiety medication. There may also be a potentially broader role for the antidepressants in the management of pure anxiety disorders, but this requires further study.

Clinical use of the antidepressants lists the more commonly used first-generation antidepressants and the oral doses needed for therapeutic efficacy in the typical patient. Currently imipramine and amitriptyline are the standards for antidepressant potency. Amitriptyline is more sedative while imipramine is more energizing. Because of the undesirable side effects observed in these original TCAs, during the past decade there has been a gradual shift among experienced clinical psychopharmacologists to the secondary tricyclic amines of desipramine and nortriptyline. The advantage of desipramine is that it has relatively fewer anticholinergic side effects, and nortriptyline appears to have a clearer relationship between plasma levels and clinical efficacy.

Before antidepressants are prescribed, a patient’s physical health must be evaluated by a physical examination and the patient should show normal values on baseline complete blood count (CBC), urinalysis, liver function tests, and (if over 45 years) an electrocardiogram (ECG). Patients are started on low doses in a twice daily regimen for 1 day (e.g., 25 mg desipramine bid) and checked for idiosyncratic reactions (e.g., postural hypotension). The dose is then raised quickly over a few days to that needed for a full therapeutic response. The minimum daily dose for clinical response is the low figure in the ranges listed, but often higher doses are needed. Physicians inexperienced in psychopharmacology should not exceed the upper dosage limits listed in the table. From 7 to 28 days are required for a full therapeutic effect to be present. Changes in the depressive symptoms are often noted by friends and family before the patient reports feeling subjectively better. A therapeutic trial of an antidepressant requires at least 28 days at the upper end of the dose range. Patients are maintained on antidepressants for approximately 8 months after the depressive symptoms disappear. Medications can be given in a single dose an hour before bedtime once an appropriate dose for a given patient has been established. The advantages of this procedure are improved medication compliance; that the sedative side effects induce sleep in depressed patients, who are often insomniac; and that the troublesome side effects occur while the patient is asleep. Some patients cannot tolerate the single bedtime dose, and in these patients a daytime twice daily or three times daily schedule is necessary.

Plasma levels of the tricyclic antidepressants are routinely available, but unfortunately the relationship of plasma levels to clinical response has been inconsistent. Linear relationships between plasma levels and therapeutic response exist for imipramine, desipramine and amitriptyline, while nortriptyline may have a curvilinear plasma level-response relationship, implying a therapeutic window. Plasma levels may be useful in treatment-resistant patients to evaluate compliance and to see if the dose is sufficient to maintain concentrations above the threshold necessary for response (e.g., imipramine > 180 ng/mL; desipramine > 125 ng/mL; amitriptyline > 95 ng/ mL; and nortriptyline 60 to 140 ng/mL).

After a number of months of treatment with antidepressants, it is recommended that the drug be withdrawn gradually over a 3- to 4-week period rather than that it be stopped suddenly. Should depressive symptoms reemerge, restoration of the antidepressant treatment is necessary for several more months, and then the withdrawal attempt can be repeated.

Side effects and interactions with other drugs some of the more common side effects from the tricyclic antidepressants; they include dry mouth, sedation, a fine tremor of the hands, and mild constipation. More serious are the effects on the cardiovascular system, where tachycardia and postural hypotension are the most common. The TCAs, especially imipramine, have a quinidine-like action, can induce cardiac arrhythmias, and have been associated with sudden death in a few patients (see section below on overdose). Patients with preexisting cardiac illness, especially those with heart block, should be treated cautiously with the TCAs, or drugs with milder cardiac effects should be considered. The most bothersome symptoms are from the anticholinergic effects; while rarely serious, they do cause discomfort and compliance problems.

Some preexisting medical conditions increase the risk of using TCAs in certain depressed patients. Tricyclics can produce tachycardia, which may push some patients from asymptomatic congestive failure into symptomatic heart failure. TCAs lower the seizure threshold and should be used cautiously in patients with seizures. The anticholinergic effects preclude TCAs in patients with glaucoma, and men with mild to moderate prostatic hypertrophy can develop urinary retention. Finally, the use of tricyclic antidepressants in patients with bipolar disorders may act to shorten the cycle length between affective episodes and may induce an acute manic episode in some patients.

The tricyclics, especially amitriptyline, imipramine, and doxepin, potentiate the effects of other CNS-depressant medications (e.g., ethanol, benzodiazepines) and patients should be cautioned about ethanol use while on antidepressants. Patients should either not drink or reduce their usual ethanol dose by one-half during tricyclic treatment. Other drug interactions include the potentiation of other anticholinergic agents (e.g., antihistamines, antiparkinsonian agents), which can result in severe constipation, urinary retention, and even paralytic ileus. This combination in the elderly can produce a serious anticholinergic blockade (e.g., paralytic ileus, fecal impaction) and not uncommonly has been the cause of frank delirium and confusional states in geriatric patients. Therefore this combination should be used with caution in the elderly.

Despite the problems, the risk/benefit ratio is overwhelmingly in favor of the antidepressants, and literally hundreds of thousands of patients have been treated with these compounds safely and effectively.

The newer antidepressant medications The development of new antidepressant medications has proceeded rapidly and many second-generation drugs are now available. More prominent second-generation drugs for which some evidence of antidepressant efficacy exists. Unfortunately, many of the clinical trials in which these drugs were studied are sufficiently flawed that the antidepressant potency of the new antidepressants has not been fully established. How these drugs will fare over time under more rigorous scrutiny is unknown. An example of the unforeseen problems which arise when promising new drugs are given broader exposure is the experience with zimelidine. This relatively selective serotonin uptake blocker was originally reported to be an effective antidepressant with milder anticholinergic side effects. With increased study it has been associated with Guillain-Barre syndrome in several patients and has now been withdrawn pending further investigation. This new generation of psychotropic medications is promising and may eventually lead to drugs that offer additional benefits.

One of the first of the new medications developed is Irimipramine, a tricyclic derivative. It has proved to be similar in its antidepressant potency and clinical spectrum to imipramine and amitriptyline. It is quite sedative and may actually have specific anxiolytic characteristics. The potential advantage of this drug is that patients may report fewer anticholinergic symptoms, even though the drug has anticholinergic properties.

Amoxapine is also a tricylic derivative with clinical efficacy equal to that of the original antidepressants. It has been claimed that this compound may have earlier onset of action (within the first week), although its clinical efficacy at the endpoint of treatment is identical to that of the original TCAs. This compound has the interesting feature that one of its metabolites (7-hydroxyamoxapine) is a neuroleptic which has been associated with the unwanted side effects seen with the antipsychotic drugs (e.g., extrapyramidal syndrome). Other side effects from amoxapine appear to be similar to those of the original tricyclics although a disproportionate number of seizures was found in some retrospective studies. It is claimed, but not yet established, that it is less cardiotoxic.

Clomipramine, a tricyclic antidepressant commonly used in Europe and Canada but not approved for use in the United States, has been shown in controlled studies to be an effective drug in the treatment of depression and to be perhaps uniquely effective in obsessive-compulsive disorders.

Mianserin is a tetracyclic derivative, but there are very few placebo-controlled studies in the United States establishing its antidepressant efficacy. There is one unpublished controlled study indicating that it is similar in its antidepressant effects to amitriptyline, but many of the studies involving mianserin have been open studies which are of dubious value in assessing its therapeutic spectrum and potency. The advantage of this drug is that it has virtually no anticholinergic side effects and little if any cardiotoxicity, but it does produce considerable sedation.

Maprotiline is also a tetracyclic derivative which is equal in antidepressant potency to the original tricyclics. It is reported to have fewer anticholinergic side effects. Originally it was offered as a promising drug for use in patients with cardiovascular problems, but this has not been established and it is not recommended for this purpose. Initially it was also felt to have less effect on the seizure threshold but it has now been reported to have caused grand mal seizures in several patients. Moreover, its use has been associated with more than the expected incidence of blood dyscrasias.

Nomifensine, a potentially interesting antidepressant related to a nonanalgesic opiate derivative, has now been withdrawn from the market worldwide because of serious hypersensitivity reactions.

Trazodone is a triazolopyridine derivative and is the first of its type to be used as an antidepressant. There is considerable controversy whether or not this drug has the same antidepressant efficacy and spectrum as the original tricyclics. The advantage of this drug is that it has few if any anticholinergic side effects. It is reported to be a potentially useful drug in patients with cardiac illness, but this has not been established. The major problems with trazodone include an unacceptable level of sedation and increased risk of priapism.

Alprazolam, a benzodiazepine derivative with proven anxiolytic efficacy, has been reported to be an effective antidepressant. It has not been established that it is as potent as the original TCAs in the treatment of major depressive disorders. It is likely to have a place in the treatment of mixed anxiety and depressive syndromes, and it has the added advantage of a more rapid onset. It has no anticholinergic effects but does cause sedation and lethargy. Since it is a benzodiazepine, withdrawal symptoms may appear after prolonged use in high dose. This is a promising new drug, which may herald the development of other benzodiazepines with antidepressant properties.

Bupropion initially appeared to be a promising antidepressant, but its tendency to cause seizures in some patients has resulted in its removal from the market for further study.

Clinical management of tricyclic overdosage Antidepressants are the fourth most common cause of drug overdose seen in emergency departments in the United States and the third most frequent cause of drug-related death (after alcohol-drug combinations and heroin). Of the antidepressants, tricyclics were the primary cause of death. In the California study (Callaham and Kassel) the annual incidence of fatal tricyclic overdose was 1.3 per 100,000 of population. More than two-thirds were women. Amitriptyline, desipramine, and nortriptyline were the most frequently implicated.

The first 6 h after an overdose of a tricyclic antidepressant are crucial. CNS depression and seizures, respiratory arrest, and cardiovascular arrhythmias are the principal causes of death. ECG changes showing QRS prolongation are early signs of toxicity, and ventricular fibrillation is a common complication. ECG changes are a more sensitive measure for monitoring patients than are blood levels of the drug.