Depression Symptoms Treatment

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Since the introduction of tricyclic antidepressants (TCAs) and the monoamine oxidase inhibitors (MAOIs) in the 1950s, the search for more effective antidepressants with fewer unwanted actions has been intense.

TCA/MAOIs were fortuitously discovered at a time when psychoanalytical and psychological theories of the etiology of depression reigned supreme in North America. The possibility that depressive disorders are ‘brain’ diseases with a pathophysiological basis was viewed with skepticism, and these medicines were largely ignored or improperly used until the late 1960s. By that time, biological theories of depression — based on the acute actions of these drugs — were becoming popular, and a waning of and disillusionment with psychoanalytic theories occurred.

Psychiatric advances have parallelled the dramatic advances in the neurosciences in the last two decades, with increasing evidence that major depressions are clearly medical syndromes with resulting central nervous system chemical/biological dysfunctions for which pharmacotherapy is the treatment of choice. Unfortunately, the public (and many physicians) have lagged a decade or two behind the research, and continue to view antidepressants as the equivalent of tranquilizers, anxiolytics, placebos or something to ‘dull’ the inherent psychological problems. To complicate the field further, in addition to the eight TCAs and three MAOIs marketed in Canada, the 1980s have witnessed the introduction of four new antidepressants with novel chemical structures, and perhaps a dozen new antidepressants will be marketed by 1990.

Definition of Depression

‘Depression’ can be a confusing word for both patients and physicians. It can refer to a mood state (both normal and pathological), a symptom present in many medical and psychiatric syndromes, and the medical syndromal disorder for which antidepressant medicine is indicated. Affective disorder is the newer name (now used by psychiatrists) for depression, which attempts to avoid some of the diagnostic confusion with the word ‘depression’.

Affective disorders are now operationally defined because older diagnostic labels which were based on understanding how and why depressed patients are the way they are (e.g., reactive depression, neurotic depression, involutional depression) have lacked reliability. A mood disturbance in addition to at least four mental or physical symptoms that are present for at least two weeks are necessary to meet criteria for major depressive disorder.

There is a dysphoric mood or loss of interest or pleasure in all or most usual activities or pastimes. The dysphoric mood is characterized by symptoms such as feeling depressed, sad, blue, hopeless, low, ‘down in the dumps’, or irritable. At least four of the following mental or physical symptoms are present consistently for at least two weeks:

• poor appetite or weight loss (when not dieting) or increased appetite or significant weight gain.

• insomnia or hypersomnia.

• psychomotor agitation or retardation.

• loss of interest in usual activities, or decrease in sexual drive.

• loss of energy; fatigue.

• feelings of worthlessness, excessive reproach or inappropriate guilt (may be delusional).

• complaints or evidence of diminished ability to think or concentrate, such as slowed thinking or indecisiveness.

• recurring thoughts of death, wishes to be dead, suicidal thoughts or suicide attempt.

What distinguishes a major depression from an ‘upset’ or ‘normal’ un-happiness related to an unpleasant life change (e.g., bereavement, divorce, loss of job, etc.) is the consistency, persistence, and severity of symptoms. The use of collateral information from a significant other (spouse, parent, close friend) is almost always necessary in order to obtain perspective on whether the patient is different from his normal self — which always occurs in depressive illness.

Antidepressant pharmacotherapy is the treatment of choice for moderately severe affective disorders, with many alternative drugs being available.

Tricyclic Antidepressants

Tricyclic antidepressants (TCAs) are the oldest and most commonly prescribed antidepressants. Three decades of research have shown that these medicines are quite effective (two-thirds of all depressed patients who receive an adequate trial of a TCA will have complete remission of depressive symptoms).  An adequate trial is considered the minimum daily drug dose for at least four weeks (see Table 1).

The eight TCAs marketed in Canada differ in their side effect profiles, with amitriptyline and doxepin being more sedative; imipramine, desipramine, and protriptyline being more stimulating; and nortriptyline, trimipramine and clomipramine being intermediate on this continuum. A prudent initial drug choice is based on a theoretical patient/drug fit (e.g., a retarded depressed patient might do best on a more stimulating TCA while an agitated patient might find a more sedating drug preferable). There are clearly individual response differences among the TCAs and if a patient does poorly (either in clinical response or toleration of drug) with a medicine, a switch to a TCA at the other end of the spectrum is appropriate.

Physicians need to be more cognizant of the financial burden to patients of different medicines. As imipramine and amitriptyline are one-half to one-third the cost of the other TCAs (see Table 1) they should be used preferentially.

In terms of cardiotoxicity of the TCAs, the most important concept is that in ‘healthy’ hearts these medicines are quite safe in therapeutic doses.

TCAs have a quinidine-like action on cardiac conduction, and while not necessarily contraindicated they must be carefully monitored in patients with cardiac conduction defects. Recent work has suggested that doxepin is no more cardiotoxic than the other tricyclics. Postural hypotension in the first month of treatment may require careful monitoring in the elderly or frail patient and is probably the most troublesome cardiac side effect of TCAs.

The atropinic complaints of dry mouth, constipation, bloating, and blurry vision occur with depressive illness and TCAs. Determining whether the problem rests with the disease or the cure can be difficult. Encouraging the patient (or perhaps the physician!) to stick with a four-week course of treatment and the nuisance side effects of the medicine often results in dramatic improvement. Palliative treatments for dry mouth, constipation, urinary retention, and sexual dysfunction will increase drug compliance.

Studies have indicated that the most common reason for ineffective antidepressant drug response is an inadequate drug trial; the minimal therapeutic dose must be given for at least four weeks. I have found that patience, persistence, and enlisting the spouse as an ally enhance the patient’s adherence to the treatment plan.

Monoamine Oxidase Inhibitors

MAOIs are effective, relatively inexpensive antidepressants that are an excellent alternative treatment for patients unresponsive to TCAs or patients who cannot tolerate the atropinic side effects of TCAs. The range, clinical profile, and monthly cost are outlined in Table 1.

The risk of a hypertensive episode associated with ingestion of foods or drugs containing pressor amines is low, and past fears of using these medicines have likely been exaggerated. Indeed, recent reports have suggested that the drug and dietary precautions while taking MAOIs can be lessened considerably, which should greatly improve compliance.

The most frequent side effect with MAOIs is not hyper- but postural hypotension which typically does not occur until two weeks into treatment.

As with TCAs, a therapeutic trial of four weeks at a minimum therapeutic dose is necessary for symptom remission.

Others Antidepressants

Maprotiline (Ludiomil)

Maprotiline, while referred to as a tetracyclic, is really a tricyclic compound with a bridge. It is a transition medicine from the TCAs to the newer antidepressants.

Studies indicate maprotiline is as effective as tricyclics in major depression, with few atropinic side effects. The dose range is similar to most tricyclics. Other than its stimulating mild atropinic drug profile, it offers few advantages over the TCAs, and it is considerably more expensive than imipra-mine or amitriptyline (see Table 1).

Trazodone (Desyrel)

Trazodone is a triazolopyridine which has peripheral a-adrenergic and 5-HT antagonistic activity with minimal anticholinergic activity. It is an effective antidepressant for mild to moderate (i.e., outpatient) depressive states, but extensive evaluations in more severe affective disorders have not been completed. It is a sedating but not atropinic medicine, and is quite expensive. The therapeutic dose is usually twice that of TCAs (300-600 mg/day). It should be considered a third-line medicine if TCAs or MAOIs are ineffective, not tolerated, or contraindicated. Data are insufficient at this time to say whether trazodone is more or less cardiotoxic than traditional antidepressants.

Nomifensine (Merital)

Nomifensine is a tetrahydroisoquinoline compound with dopaminergic/noradrenergic activity and minimal anticholinergic activity. There are relatively few North American studies on the efficacy of nomifensine, although the completed work suggests that in doses of 100 to 250 mg/day, nomifensine is as effective as TCAs in treating major depression.18 Side effects may include insomnia, headache, and an unpleasant motor agitation. I feel that the jury is still out on the advantages of nomifensine over TCAs and MAOIs, and that nomifensine should be selected as a third-line drug for depression.

Amoxapine (Asendin)

The dibenzoxapine amoxapine is the demethylated derivative of the neuroleptic loxapine. It has strong adrenergic and weak neuroleptic properties. Studies indicate it is as effective as tricyclics in doses of 300-600 mg/day, but the early claims of a faster onset of action have not been replicated.

I believe the equivalent safety of amoxapine is less when compared to other antidepressants as first-line treatments. Neuroleptics should be avoided in depressive illness because of the risk of tardive dyskinesia, and extra pyramidal side effects do occur with amoxapine. An alarming number of deaths from amoxapine overdoses (when compared to tricyclic overdoses) have been reported, suggesting amoxapine may have a lower therapeutic index than tricyclics.

Conclusions

In summarizing the new antidepressants, it appears they may be as effective as the TCAs and MAOIs, but clearly are not more so. The new medicines often have different side effects from the older ones, which may or may not offer clinical advantages. These drugs are considerably more expensive.

Accordingly, my choice of which antidepressants to use is still the tricyclics. Imipramine (if the patient’s depressive symptoms are more retarded or hypochondriacal) or amitriptyline (if the patient’s motor activity is more agitated) are first choices in major depressive disorders. If the TCA is ineffective or intolerable, then an alternative TCA or an MAOI is indicated. Emphasis on the necessity of an adequate therapeutic trial to the patient and his family, frequent reassurance of future symptom relief, education for patient and family about the nature of the illness, and treating nuisance side effects when they occur lead to symptom remission in well over 90% of all patients.

Résumé

(French Language)

Au Canada, le marché des antidépresseurs comprend actuellement 15 antidépresseurs efficaces (huit tricycliques, trois inhibiteurs de la mono-amine oxydase et quatre médicaments dont la structure chimique est nouvelle). Les tricycliques demeurent encore le premier choix dans le cas des dépressions majeures à cause de leur efficacité prouvée sur une période de plus de trente ans, le profil bien connu de leurs effets secondaires et le coût inférieur de l’imipramine et de l’amitriptyline comparativement aux autres tricycliques et aux nouveaux antidépresseurs. Les inhibiteurs de la mono-amine oxydase sont une excellente alternative et sont beaucoup plus sécuritaires que ne l’avaient suggéré certains rapports antérieurs. La maprotiline ne présente que peu d’avantages comparativement aux tricycliques et est significativement plus coûteuse. Le trazodone peut faire partie des médicaments de deuxième ou troisième choix, l’avantage étant son peu d’effets anticholinergiques. On n’a pas encore procédé à une évaluation clinique adéquate de la nomifensine. Quant à l’amoxapine, ses propriétés neuroleptiques et cardiotoxiques suggèrent de prescrire en premier lieu d’autres médicaments.