It is well recognized that depressive disorders are very common in general practice. Estimates of the prevalence of depression vary, but a recent estimate puts the figure at approximately 10%. Only a small percentage, less than 10%, of depressed patients in primary care are referred to psychiatric services. Thus 90% of depressed patients are probably treated by family physicians. It is therefore critical that family physicians be skilled in recognition and management of depression.

There are a significant number of failures in the treatment of depressed patients, for although in principle the treatment of depression with medication should be very straightforward, in practice there are specific difficulties that make the treatment more of an art than a science. These difficulties relate to a number of factors, namely:
• the determination of appropriate indications for antidepressants;
• the selection of an appropriate drug;
• the latency of the therapeutic effect;
• troublesome side-effects; and
• compliance, which is directly connected to the two points last mentioned.

The purpose of this article is to condense the essential and key components necessary for the successful use of tricyclic antidepressants. These components fall into two main categories:

• the use of the drug itself; and
• the psychotherapeutic function of the physician during drug treatment.

The Use of the Drug

Appropriate indications

The physician’s ability to diagnose correctly a medication-responsive depression is hampered by a confusing array of terminologies. Despite the recent improvements as a result of the introduction of DSM-III, many different terms are still employed, for example, “endogenous”, “reactive”, “neurotic”, “psychotic”, “major depression”, “dysthymia”, “mixed anxiety-depression”, “adjustment disorder with depressed mood”, “unipolar”, and “bipolar”.

Regardless of which terminology is preferred, the decision to use antidepressant medication should be based on the pattern and severity of certain symptoms, as well as on previous history of response. This applies also to the situation where there appear to be justifiable reasons for the depression. The fact that there may be external psychosocial stresses that can account for the depression does not rule out the successful use of antidepressants. The best predictors of a good response to antidepressants are the presence of two or more of the following symptoms:
• early morning awakening;
• diurnal variation: the person feels significantly worse in the morning;
• a feeling of dread or extreme anxiety or agitation in the morning;
• a loss of pleasure in all activities;
• a lack of reactivity of the mood to changes in circumstances;
• psychomotor retardation;
• significant weight loss;
• depression that is characterized by feelings of blackness, despair, extreme hopelessness, and pessimism.

Other factors that predict a good response are a family history of depression that has responded to medication or to electroconvulsive therapy (ECT), and a history of a previous response to antidepressant medication or ECT.

Choice of drug

This review is confined to a discussion of tricyclic antidepressants. In general, indications for other antidepressants or special combinations of medications will require specialist referral.

Competing manufacturers’ claims about newer antidepressants complicate the physician’s choice. In practice, however, the newer agents are usually no better than the older, established drugs. It is true that the side-effect profiles of the new agents may be more favorable, but in many cases their clinical efficacy is disappointing. Careful review of many of the studies shows that in clinical trials newer drugs have been compared to inadequate dosages of standard medications. In addition, clinical trials are often of short duration — perhaps lasting four weeks — so that the full effect of the standard antidepressant may not have become evident, since it can take up to six weeks to reach this full effect.

For the physician to have confidence in his or her choice of a drug, it is important that he or she has had good results with previous use of the drug. Therefore, it is wise to limit the use of tricyclic antidepressants to two or three and to become confident in their efficacy. Like old wines, some of the older antidepressants are best; for example, amitriptyline and imipramine are extremely effective and extremely well established. Desipramine has also become a very popular antidepressant because of its effectiveness and lower incidence of anti-cholinergic side-effects.

Much research has been devoted to determining patient response to a variety of antidepressants on the basis of their biochemical properties and to attempting to subtype depressive disorders on the basis of measurable neurotransmitter metabolites. The results of these studies are not consistent enough to justify their use in routine clinical practice.

Effective dosage

In psychiatric practice, it is found, in general, that a minimal dose of 150 mg of a standard tricyclic is required for effective treatment. There is a caveat, however: most studies have been done on psychiatric patients who may represent the more severely depressed 10% of the full spectrum. Therefore, it may be that among a general practice population there are milder forms of depression that respond to lower doses of tricyclics. Nevertheless, where there is evidence of significant severity of symptoms, the optimum dosage would be 150 mg. This does not apply, however, to elderly patients, for whom dosages of one-third to one-half this amount are recommended. The elderly are more sensitive to side-effects of the medications and eliminate the drugs more slowly.

Another principle with respect to effective dosage is that the patient must remain on the same dosage for a minimum of three weeks, and probably four weeks, in order to allow the physician to assess response. There may be no evidence of improvement prior to the three- to four-week point other than in sleep pattern. It is clearly important that the patient be made aware of the medication’s latency.

In recent years there has been a trend towards using blood levels to determine appropriate dosage. This is still a problematic practice and is very often unnecessary in straightforward cases seen in routine clinical practice. Blood-level monitoring does have a place, however, in complex or non-responsive cases.

Management of troublesome side-effects

It is wise for the physician to keep in mind, in all cases, contraindications to the use of tricyclics and potential drug interactions. In view of the multitude of new medications that are constantly coming into use, it is prudent to consult a reference text periodically to keep abreast of potential drug interactions. In general, side-effects of tricyclics tend to be more troublesome than dangerous: dry mouth, constipation, urinary slowing, over-sedation, and hypotension.

The best approach to dealing with these side-effects is through prevention. Prevention involves initiating treatment at small doses (i.e., 25 mg HS) and then assessing the patient’s tolerance for the medication. If the initial dose is well tolerated, the dosage should be increased by 25 mg HS every two or three nights, depending on tolerance, until the full dose of 150 mg HS is reached. If the patient appears sensitive to side-effects or cannot tolerate the discomfort, the dosage can be increased more slowly, or treatment can be initiated at lower levels (e.g., 10 mg HS). Again, the patient needs to be reminded that he or she will have to be on the therapeutic dose of 150 mg or more for at least three weeks in order to establish a response.

There is one particular side-effect that is very troublesome: a paradoxical increase in arousal level at the initiation of even small doses of tricyclics. This seems noticeable with the use of imipramine and clomipramine in particular and occurs most often in patients who have anxiety or panic symptoms. These patients will describe a worsening of these symptoms, a feeling of arousal, jitteriness, a sense of being “speeded up”, and a sense that their head is bursting or about to explode. In such patients, the physician can attempt to initiate treatment at very low dosages or to mask the side-effects with a benzodiazepine, such as lorazepam or chlordiazepoxide, during the first few weeks of treatment. If the patient can tolerate these side-effects for a week or two, they tend to abate. However, treatment often has to be discontinued. The patient may be able to tolerate an alternative tricyclic.

Finally, it is worth remembering that where there is a risk of overdose, the quantity of medication prescribed at one time should be kept small. The physician should avoid giving open-ended repeat prescriptions; otherwise, if the patient’s condition worsens and includes development of suicidal ideation, he or she would have ready access to a large supply of lethal medication.

Psychotherapeutic Functions

First and foremost is the physician’s establishment of a trusting, empathic, and non-judgmental relationship with the patient. It is critical that the physician take enough time to listen to the patient’s distress and to respond to it supportively.

Educating the patient about depression is also critical. It is important for the patient to understand that there is a biological component to his or her illness, and that this component is the reason for the use of medication. Depression is, in fact, very often a physical illness that affects numerous bodily functions such as sleep, appetite, weight, and sex drive. Understanding the biological nature of depression helps the patient by reducing his or her feelings of self-blame and self-criticism, and the belief that he or she is weak, inadequate, or unintelligent. Written material explaining the nature and treatment of depression is very helpful and should be distributed to the patient and to members of his or her family.

The patient must be educated about the critical nature of the dose of medication and must be told that he or she will have to build up slowly to the effective level. It is vitally important that the patient understand that there will be a three-to four-week period of latency; otherwise, the patient will discontinue treatment after a few days, believing that the medication is useless and ineffective. Alternatively, the patient may become extremely disappointed at the lack of response and may begin to feel more hopeless and suicidal.

The physician should educate the patient about common side-effects of the medication and should recommend strategies for dealing with these, such as chewing sugar-free gum to relieve a dry mouth; the use of bran cereals and fibre supplements to prevent constipation; the need to rise slowly from a sitting or lying position for patients who have postural hypotension.

Ongoing support and monitoring is essential. In the early phases of treatment, the physician should see the patient at least once a week to provide support and reminders about the latency of treatment effects, and to deal with any disappointment or discouragement the patient may feel because of the slowness of response. The patient’s depressive symptoms and suicide potential should be assessed at each visit.

The nature of the recovery process must be explained to the patient. Often there are changes on the “outside” first. There may be an early improvement in sleep pattern. The patient appears brighter, more alert, and may begin to pay more attention to grooming and appearance. However, in these early stages of improvement there may be little, if any, subjective improvement in mood. Consequently, the patient may become irritated or discouraged when friends or the physician comment that he or she is improving. The patient may feel that people are trying to give him or her false reassurance and hope, and may, in fact, become more discouraged and hopeless. This problem can be averted if the physician informs the patient, in advance, of the possibility of its occurrence. The patient must also be warned that recovery does not always occur in a straight line: that is, he or she may begin to feel some temporary lifting of the depression only to find that his or her mood drops back to previous levels. The recovery process is often “up and down” in this way. In general, the trend is that the “up” periods become more frequent and of longer duration, and the “down” periods diminish. The patient, after some temporary improvement, very often becomes more despondent and hopeless when the depression returns. Therefore, it is very important that the patient be forewarned of this probability and be reminded that the “up-and-down” cycle, when it occurs, is temporary.

If the patient does respond successfully to treatment, he or she should be maintained on the antidepressant for approximately six months to a year. Early discontinuation of medication is associated with relapse. There is no way of determining with certainty how long a patient should continue on medication, but at some point between six months and a year, an attempt can be made to reduce the dose gradually by 25 mg every two to three weeks. Should there be any signs of recurrence of symptoms, the treatment should be reinstituted at the former dosage.

It has been common practice to reduce the antidepressant dosage to a maintenance level after two to three months. However, as there is no way of predetermining an adequate maintenance level, it is generally more effective to maintain the dosage at the therapeutic level of 150 mg.

In those patients who have not responded to a daily dose of 150 mg by the end of a four-week trial, the dose can be increased by 25-mg increments up to 200 mg HS for a further two to three weeks. If the patient fails to respond at this point, he or she probably warrants referral to a specialist.

Conclusion

By following the principles outlined above, the family physician will find that he or she can successfully treat in general practice cases of moderate to moderately severe depressive disorder. The treatment of such conditions can be extremely rewarding and can have an enormous effect on the patient and his or her family. Depressive disorder can be one of the most distressing and unpleasant subjective experiences, and the family physician can derive immense satisfaction from its alleviation.

RÉSUMÉ

La dépression est le problème psychiatrique le plus courant auquel sont confrontés les médecins de famille. La prévalence de dépression chez les patients d’une pratique familiale est de l’ordre de 10%. La plupart des cas de dépression sont traités par les médecins de famille. Par conséquent, il est essentiel que ces derniers soient tout à fait familiers avec l’utilisation efficace des antidéresseurs. Cet article passe en revue les différentes composantes essentielles à l’utilisation efficace des antidépresseurs. L’auteur discute des indications, dosage et durée de traitement appropriés et des fonctions psychothérapeutiques du médecin.

Handbook of Depression. Second Edition

EE Beckham, WR Leber, editors

New York: Guilford Press; 1995. 628 p

This multiauthor book is edited by E Edward Beckham, PhD, and William R Leber, PhD, both associate professors in the Department of Psychiatry and Behavioral Sciences at Oklahoma University. Its 628 pages contain 5 sections and 2 appendices: 1) Defining the Boundaries of Depression (epidemiology, diagnostic classification, assessment of severity and symptom patterns, and relations to other Axis I, Axis II, and Axis III disorders); 2) Biological Processes and Treatments (genetics, biological processes, somatic therapies including drugs, and medical diagnostic procedures); 3) Psychological Therapies (cognitive, behavior, interpersonal, analytic, couple and family, integration, and comparing and combining psychotherapy with pharmacotherapy); 4) Special Populations (children and adolescents, geriatrics, people at risk for suicide, women); and 5) Psychological and Social Contexts (life context and coping processes). The appendices provide information on rating scales available for assessment of depression in children and adults, the adult section including the full Hamilton and Zung rating scales.

This book largely succeeds in its goal of offering a comprehensive and up-to-date review of the field. As a 2nd edition, a number of chapters are polished updates of the 1st edition, and the approach is a scholarly one with plentiful references.

The 1st section on epidemiology, diagnosis, and comorbidity deals successfully with difficult conceptual issues. It also provides useful sections on depression and cancer and other important cardiovascular, neurological, endocrinological, and immunological diseases, including treatments.

The chapter on genetics is restricted, surprisingly, to bipolar illness, in a book otherwise devoted to depression. The chapter on biological processes in depression is substantial (at 66 pages with references) and excellent. The identification of melancholia as a black mood rather than black bile in discussing the views of Hippocrates suggests that the editors need a brushup in the classics!

Treatment for depression is overly weighted toward the psychological therapies, with 6 chapters on psychotherapies, 1 on somatic therapy, and 1 on the combination. The chapter on somatic treatments, brief at 22 pages, succeeds best in its description of the pharmacology of antidepressant drugs. For the psychiatrist reader, the book would have benefitted from separate chapters on electroconvulsive therapy and treatment-resistant depression. Electroconvulsive therapy receives only one-half page, with no reference more recent than 1989 and no reference to the important work of Harold Sackeim and his coworkers at Columbia University. Only a page and a half are given to the treatment of resistant depression; no mention is made of leucotomy, and the references for thyroid hormone augmentation of antidepressant medication are no more recent than 1984, ignoring, for example, recent contributions by Russell Joffe and colleagues. Regarding some statements and recommendations in this chapter, some changes would be advisable: 1st, it takes several weeks (rather than days) to recover normal function of monoamine oxidase after discontinuation of irreversible monoamine oxidase inhibitors; 2nd, 3 to 4 weeks (rather than 2) should elapse after discontinuing an irreversible monoamine oxidase inhibitor before starting serotonin reuptake inhibitors, particularly clomipramine and venlafaxine; and 3rd, it can take considerably longer than 5 weeks for adequate washout of fluoxetine in some patients, and fluoxetine plasma levels can assist in determining when it is safe to commence an irreversible monoamine oxidase inhibitor.

While based on a level of scientific rigor no more advanced than a review of cases treated, the chapter on long-term analytic treatment contains a review of the developments in the psychoanalytic theory of depression and some case descriptions that would be of value to students. The authors assert that “medication ameliorates the more biologically based symptoms (e.g., early morning insomnia, anorexia, or anergia), whereas psychotherapy exerts an effect on the individual’s more psychological functions (e.g., social withdrawal, suicidality, or low self-esteem)” and advocate medication in appropriate cases to permit successful psychotherapy. While it is clear that many patients with depression require psychotherapy in conjunction with medication and that successful pharmacotherapy often creates ideal conditions for successful psychotherapy, it is also clear that medication alone can completely resolve severe “psychological” symptoms of depression, and recent research shows that fluoxetine can even lift mood in normal subjects.

The chapters on special populations are generally balanced and comprehensive. The chapter on women and depression concludes that the female:male ratio for depression of 2:1 is accounted for by social and psychosocial factors rather than biological ones and ends with the warning that DSM nosology may be “a means of perpetuating a white male Eurocentric understanding of what constitutes mental health for this world’s population.” This chapter seemed somewhat 1-sided, but perhaps that is because this reviewer is a biologically oriented white male psychiatrist of European descent!

While the book does appear to have been carefully reviewed and proofed, small errors are inevitably present in a book of this size and scope. For example “ondanserton [sic]” is identified as a 5-HT3 agonist rather than an antagonist at this receptor, and tertiary and secondary amine tricyclics are said to have 3 and 2 methyl groups respectively, rather than 2 and 1.

On balance, the strong points of this book outweigh its weaknesses. It would be a valuable addition to libraries (health sciences, psychology) and would be useful to students in the clinical psychological sciences (psychiatry, clinical psychology) and clinicians and researchers with an interest in depression.

Major depression affects 5% to 10% of patients seen by primary care physicians. Despite the advent of new antidepressant drugs, up to 20% of patients remain fully resistant to treatment and a further 20% to 30% only partly respond to treatment. Therapy should aim at eradicating depressive symptoms completely (i.e., complete remission) because incomplete recovery is associated with continued functional impairment and a greater risk of relapsing to full-blown depression. One way to approach treatment of major depression is through the mnemonic, OSCAR, which highlights the five steps for treating depressed patients: Optimization, Substitution, Combination, Augmentation, and Review. While optimization is always the first step, there is no clear consensus on what the next step should be if optimization fails.

Quality of evidence

Relevant articles were identified by MEDLINE search from 1966 to January 1999. MeSH headings included depression, combination, augmentation, lithium, triiodothyronine, pindolol, buspirone, methylphenidate, and electroconvulsive therapy (ECT). The search was limited to English-language articles on human subjects aged 18 years and older appearing in well-recognized, peer-reviewed medical journals. Studies were critically reviewed, references from papers retrieved were scrutinized for other relevant reports, and all were combined with studies in the author’s personal files.

Article selection was based on clinical relevance and study design. The recommendations of the Canadian Network for Mood and Anxiety Treatment, the clinical practice guidelines of the United States Department of Health, and product monographs of antidepressants were analyzed.

Optimization

Optimization is prescribing an antidepressant in the best possible way. Optimization of dose (must be adequate) and length of time a patient remains on the adequate dose are important. Optimization includes encouraging compliance, which improves when patients are educated about their illnesses and medications. Optimization includes attention to psychosocial stressors that might contribute to the illness. The effect of the illness on a spouse, children, friends, and employment should be addressed.

Before prescribing any antidepressant, accurate diagnosis is essential. Depressive symptoms can occur in conditions other than major depression (e.g., alcohol abuse) and might be secondary to medical conditions or medications.

First-line antidepressants. Antidepressants are classified according to their presumed mechanisms of action (Table 1). Each antidepressant affects one or more of three neurotransmitters: serotonin (5-hydroxytryptamine [5HT]), norepinephrine (NE), and dopamine (DA). No compelling data indicate that one antidepressant is more effective than another, and choice depends on other issues, such as tolerability, safety in overdose, interaction with other drugs, and cost. When depression is severe, however, antidepressants affecting both serotonin and norepinephrine (eg, tricyclics [TCAs], venlafaxine) might be more effective at relieving symptoms.

Dosing strategies.Selective serotonin reuptake inhibitors (SSRIs), such as sertraline, paroxetine, citalo-pram, and fluoxetine, are usually initiated at doses that are ultimately the usual therapeutic doses (i.e., 50, 20, 20, and 20 mg/d, respectively). Fluvoxamine is started at 50 mg/d for the first week (to reduce nausea) and then increased to 100 mg/d, its usual therapeutic dose. When depression is associated with marked anxiety, SSRIs are initiated at a lower dose to prevent early worsening of anxiety symptoms. Some patients metabolize SSRIs quickly and, therefore, when they do not respond after 4 weeks, dose should be increased. The new dose should be continued for at least 1 week before increasing further. Usual maximum dose for fluoxetine, citalo-pram, and paroxetine is 60 mg/d, for sertraline is 200 mg/d, and for fluvoxamine is 300 mg/d.

Tricyclics are started at 50 mg/d with dose increased every third day until 150 mg/d is reached. If there is no response by 4 weeks, dose should be increased by 50 mg/d every 5 days until response occurs or side effects intervene. The usual maximum dose for TCAs is 300 mg/d. Nortriptyline is an exception because it loses its efficacy when doses exceed 100 mg/d.

Nefazodone is most effective when prescribed in doses of 300 to 500 mg/d. Nefazodone is initiated at 50 mg bid so patients can become accustomed to the medication; nefazodone is usually given twice daily because of its short half-life (3 hours).

Monoamine oxidase inhibitors (MAOIs) require a tyramine-free diet and the risk of interaction with other drugs demands caution. The usual therapeutic dose range for phenelzine is 45 to 90 mg/d; the range for tranylcypromine is 20 to 60 mg/d. With half-lives of 2 hours, MAOIs are given in divided doses.

Moclobemide does not inactivate the enzyme that metabolizes tyramine and, thus, there are no dietary restrictions. The therapeutic dose of moclobemide is 450 to 600 mg/d; the drug is usually given twice daily because of its half-life of 1 hour. Starting dose is 150 mg morning and evening with gradual increase to a maximum of 600 mg/d.

Venlafaxine extended release is commenced at 75 mg/d, although patients sensitive to side effects might benefit from a 37.5 mg/d dose for 4 to 7 days before increasing to 75 mg/d, the usual effective dosage for mild to moderately depressed outpatients. There is a significant relationship between increasing dose and increasing efficacy. If response is incomplete by 4 to 6 weeks, the dose may be increased incrementally to a maximum of 225 mg/d. Increases should occur no more frequently than every 1 to 2 weeks, increasing by 37.5mg to 75mg on each occasion.

Bupropion sustained release is initiated at 100 to 150 mg once daily in the morning, increasing to a maximum of 300 mg/d if response is poor. Doses greater than 150 mg/d should be given bid, preferably with at least 8 hours between doses.

Adequate duration of an antidepressant trial. Once dose has been optimized, it is important that patients remain on the adequate dose for sufficient time. A trial should last at least 6 weeks because it usually takes 4 to 6 weeks before response to an anti-depressant occurs. If a patient does not respond at all by week 6, or if the response is only partial, diagnosis, medication dose, and compliance should all be reviewed and other treatment options considered.

Substitution

Substitution (or switching) is replacing an ineffective drug with a new drug. Switching to a new agent keeps things simple and avoids potential drug-drug interactions. Monotherapy might also be associated with greater compliance.

Controlled studies have shown that when patients are switched from one TCA to another TCA (i.e., to an antidepressant of the same class) the response rate is only 10% to 30%. When double-blind studies examined patients’ switching to different classes of antidepres-sants (e.g., SSRI to TCA), however, response rates were higher at 40% to 70%.

Open-label studies suggest that when patients fail to respond to one SSRI they might respond to a different SSRI. The value of switching from one SSRI to another, however, is controversial, and further studies are needed to determine the effectiveness of this strategy.

Most antidepressants can be switched quickly but, even when no washout period is required, good clinical practice recommends tapering and stopping one antidepressant before starting the next medication. In situations where time is important, the next medication can usually be started and increased while tapering the old medication. Rapid switching minimizes the time required to obtain relief from depressive symptoms.

When switching from an MAOI to any other drug, a washout period of 2 weeks is required; when switching from moclobemide, a washout period of 3 days is recommended. When switching to an MAOI or moclobemide from any other drug, a washout period of 1 week (5 weeks for fluoxetine) is required.

Some SSRIs elevate TCA levels by inhibiting enzymes that metabolize TCAs. When switching from an SSRI to a TCA, introduce the TCA at a lower dose. Similarly, before switching to an SSRI, it is wise to reduce the dose of a TCA

Combination

Combination is the prescription of two antidepressants, each from a different therapeutic class and each, supposedly, with its own unique mechanism of action. It is assumed that the unique effects of each drug will cumulatively interact to provide a greater therapeutic effect than either drug alone.

One study reported a 65% response rate when patients poorly responsive to fluoxetine had a low-dose TCA added to fluoxetine. In a similar open retrospective trial, an SSRI-TCA combination yielded a 35% response rate. In a double-blind study, only 25% of patients resistant to treatment with fluoxetine responded when low-dose desipramine was added. Further controlled studies are needed to clarify the effectiveness and usefulness of this strategy. The SSRI-TCA combinations are potentially dangerous due to the ability of SSRIs to increase TCA plasma levels, and TCA levels must be monitored in these situations.

Novel antidepressant combinations include SSRIs and moclobemide and SSRIs and bupropion. Such combinations should be prescribed by physicians with expertise in psychopharmacology.

Augmentation

Augmentation is addition of an agent to boost or magnify the effects of the original antidepressant. The new agent is not considered an antidepressant when used alone. Augmentation might be preferred by patients who have had some degree of response to an antidepressant and who are reluctant to risk losing this improvement. Augmentation might also work more quickly than switching.

Lithium.Almost all placebo-controlled studies found lithium to be more effective than placebo; response to lithium was about 50%. Although most of the original studies were done with TCAs, more recent placebo-controlled studies demonstrate that lithium augmentation is also effective with SSRIs.

The efficacy of lithium augmentation appears to depend on achieving adequate serum lithium levels (0.4 to 1.0 mEq/L) and a dose of 900 mg/d is usually required. Lithium augmentation of fluoxetine can produce marked gastrointestinal adverse effects, and lithium should, therefore, be initiated at a low dose when augmenting SSRIs. Lithium augmentation should be continued for 6 weeks before deciding that treatment is ineffective.

Thyroid hormone. In several, but not all, open and controlled studies, T3 (triiodothyronine) augmented the response to TCAs, with positive studies reporting a success rate of up to 50%. In one report, T3 successfully augmented the responses of three patients receiving fluoxetine. For augmentation, the usual dose of T3 is 25µg/d. When effective, T3 acts within 2 to 4 weeks.

Pindolol. Following administration of SSRIs, the concentration of serotonin (5HT) in the synaptic cleft increases. This results in stimulation of presynaptic receptors that causes a decrease in 5HT release through negative feedback. Pindolol blocks these receptors and might augment antidepressant activity by inhibiting negative feedback. Several open-label studies support this theory, but only three of six randomized controlled trials clearly demonstrate benefits from addition of pindolol to an SSRI. Further investigation is required.

Buspirone. Several open-label studies suggest that buspirone (20 to 50 mg/d) is effective in augmenting the antidepressant effects of SSRIs. The only placebo-controlled study, however, found no difference between buspirone and placebo.20 In that study, the placebo response was particularly high (46.7%), and further studies are required to reliably determine buspirone’s efficacy as an augmentor of SSRIs.

Stimulants. There are no controlled studies examining the role of stimulants as augmenting agents. In a recent open trial, methylphenidate successfully augmented all of five patients with poor response to SSRIs. Further studies are required.

Electroconvulsive therapy. For patients who fail to respond to adequate trials of antidepressants, the response rate to ECT is approximately 50%. Unfortunately, 60% of these ECT responders relapse within 1 year, usually within the first 4 months.

L-tryptophan. Controlled studies confirm the ability of tryptophan (the precursor of 5HT) to augment the antidepressant effects of MAOIs, but the risk of toxic interaction makes this strategy hazardous. There is insufficient evidence in support of tryptophan’s capacity to enhance the efficacy of SSRIs or TCAs.

Psychotherapy. The pharmacological treatment of depression usually occurs in the context of a psychotherapeutic relationship. When a patient is not responding, reconsider psychotherapeutic strategies. Cognitive therapy might improve the response of patients resistant to treatment with antidepressant medication alone.

Review (and referral)

When response remains poor despite some of the strategies described above, the steps taken should be reviewed, including reassessing the diagnosis and the possibility of comorbid conditions. Referral to a psychiatrist is appropriate when treatment fails or when diagnosis is unclear. Referral should be made on an urgent basis when a patient becomes suicidal or psychotic.

Key points

• The mnemonic OSCAR refers to five steps for treating depressed patients: optimization, substitution, combination, augmentation, and review.

• Optimization means choosing an appropriate antidepressant, building to the correct dose, and allowing sufficient time for it to work.

• Substitution is replacing an ineffective drug with a new one.

• Combination is usually of two antidepressants from different therapeutic classes (e.g., selective serotonin reuptake inhibitors and tricyclic antidepressants) and should be approached cautiously.

• Augmentation adds an agent, such as lithium, thyroid hormone, pindolol, buspirone, or electroconvulsive therapy, to boost the effect of an antidepressant.

• When all else fails, review the case and consider referral.

Résumé

(French Language)

Objectif

Examiner la pharmacothérapie contre la dépression et évaluer les stratégies de traitement actuelles en vue de tirer profit au maximum des avantages des médicaments antidépresseurs.

Qualité Des Données

Une recension dans MEDLINE a été effectuée jusqu’à janvier 1999 à l’aide des rubriques en anglais pour dépression, combinaison, augmentation, lithium, triiodothyronine, pindolol, buspirone, méthylphénidate et électrochoc, pour trouver des essais aléatoires contrôlés, des aperçus systématiques et des rapports de consensus. Des études récentes de grande qualité ont souvent été relevées. Les références citées dans les articles retenus ont fait l’objet d’un examen pour trouver d’autres rapports pertinents. La préférence a été accordée aux articles plus récents et aux études bien conçues. Les recommandations de groupes scientifiques ont été analysées.

Principal Message

La pharmacothérapie contre la dépression repose sur l’optimisation de la thérapie antidépressive. Lorsque les symptômes persistent malgré l’optimisation, figurent au nombre des autres stratégies possibles la substitution, la combinaison, l’augmentation, la révision et parfois l’aiguillage. Les décisions se fondent sur les données probantes à l’appui des diverses stratégies.

Conclusions

Les antidépresseurs ne fonctionnent que lorsqu’ils sont prescrits correctement. Une sensibilisation aux stratégies d’utilisation des antidépresseurs et d’évaluation de leur efficacité rehausse la capacité des médecins de première ligne de traiter cette affection courante.

Points de repère

• Le sigle mnémonique OSCAR représente les cinq étapes du traitement des patients dépressifs: l’optimisation, la substitution, la combinaison, l’augmentation et la révision.

• L’optimisation signifie choisir l’antidépresseur approprié et la dose correcte, et accorder suffisamment de temps pour permettre à l’agent de fonctionner.

• La substitution consiste à remplacer un médicament inefficace par un nouveau.

• La combinaison se traduit habituellement par le recours à deux antidépresseurs de classes thérapeutiques différentes (p. ex. certains inhibiteurs du recaptage de la sérotonine et les antidépresseurs imipraminiques) et elle devrait être adoptée avec prudence.

• L’augmentation veut dire l’ajout d’un agent, comme le lithium, l’hormone thyroïdienne, le pindolol, le buspirone ou l’électrochoc, pour amplifier l’effet de l’antidépresseur.

• Quand tout le reste a échoué, il faut revoir le cas et examiner la possibilité d’un aiguillage.

Research question

Is sertraline (Zoloft) effective at improving the symptoms and reducing the functional impairment associated with premenstrual dysphoric disorder (PMDD)?

Type of article and design

Prospective, multicentre, double-blind, randomized placebo-controlled trial.

Relevance to family physicians

As defined by DSM-IV criteria, PMDD has a group of physical and behavioural symptoms that occur during the premenstrual period and are severe enough to interfere with work, usual activities, and relationships. Premenstrual syndrome (PMS), on the other hand, has milder physical and behavioural symptoms (breast tenderness, bloating, headache, and minor mood changes). Studies have documented that about 20% to 40% of women experience premenstrual symptoms, but only about 4% to 8% of women have PMDD. The quality of life of patients with PMDD would improve substantially if medical therapy could alleviate its physical and psychological symptoms and reduce functional impairment.

Recent clinical trials suggest that progesterone (Prometrium) or oral contraceptives are no more effective than placebo for treating PMDD. Although short-acting benzodiazapines, such as alprazolam (eg, Xanax), have been effective in improving symptoms, their addictive potential limits their use. Researchers have postulated that PMDD, like major depression, might be associated with neurotransmitter dysfunction. Recent clinical trials have shown improvement of PMDD symptoms with agents that block serotonin reuptake (fluoxetine [eg, Prozac], paroxetine [Paxil]), but have not addressed patient-oriented outcomes, such as changes in lifestyle, relationships, and functioning.

Premenstrual dysphoric disorder is at the more severe end of a spectrum of illness that affects many women. We suspect many of our patients endure the symptoms and that family doctors often fail to inquire because both parties want to minimize the disease, given the social stigma surrounding premenstrual symptoms. Does this trial indicate a treatment for those with severe symptoms?

Overview of study and outcomes

A total of 447 women were recruited either through advertisement or by referral from psychiatric outpatient clinics or gynecology departments. Patients had to be 24 to 45 years old, have regular menstrual cycles lasting 24 to 36 days, and have at least a 2-year history of PMDD for study entry. Patients were excluded if they met criteria for other mood, anxiety, or eating disorders in the last 6 months, had a history of alcohol or drug abuse within 12 months, or had a lifetime history of psychotic disorders or organic mental syndromes. Patients underwent two diagnostic screening assessments. Those who failed to confirm isolated luteal-phase symptoms for at least two cycles on daily symptom ratings (consistent with DSM-IV criteria for PMDD) were excluded. In all, 277 women entered the next phase of the study in which all patients received placebo for a full menstrual cycle. This phase was designed to weed out those who had an apparent response to an intervention (in this case placebo) rather than a genuine response to a therapeutic agent. Next, 243 patients were randomized in a double-blind fashion to receive either placebo or sertraline at 50 mg daily for three menstrual cycles. Sertraline doses were increased upward by 50 mg after each cycle if response was insufficient (at physicians’ discretion).

The primary end point of the study was change from baseline in patients’ total mean score in their Daily Record of Severity of Problems. This record is a 24-item questionnaire that elicits information on the physical and psychological symptoms of PMDD (DSM-IV) and on areas of functioning, such as productivity at work, home, and school and interference with hobbies, social activities, and relationships. An intent-to-treat perspective was taken in the analysis.

Secondary end points included Hamilton Rating Scale for Depression scores and response to treatment as measured by the Clinical Global Impression (CGI) scale. In addition, functional impairment affecting personal relationships and work was measured by the Social Adjustment Scale.

Results

Patients in both treatment arms were similar at baseline. Mean age of patients was 36 years, and mean duration of PMDD was 9 to 10 years. About 40% of patients had a history of major depressive disorder, and 25% had a history of postpartum depression.

The DRSP total scores decreased significantly (P<.001) in the sertraline-treated group (from 64 ± 22 to 44 ± 19, 32%) compared with the placebo-treated group (from 62 ± 22 to 54 ± 24,11%). Lower scores indicate improvement. It is interesting to note that DRSP total scores in the placebo-treated group decreased considerably from baseline to end point. The authors suggest this trend could be due to “hypervigilance” in the setting of a clinical trial. According to the CGI scale, 62% of the sertraline-treated group and 34% of the placebo-treated group responded to therapy (P<.001). Evaluation of functional impairment revealed that productivity was 38% less impaired for the sertraline group and 13% less impaired for those receiving placebo (P<.001); hobbies and social activities were hindered 38% less and 17% less (P<.002), and relationships improved by 42% and 15% (P< .001) in the sertraline-and placebo-treated groups, respectively.

Sertraline was well tolerated generally (18% of adverse events were considered severe in the sertraline group, 14% in the placebo group). Patients receiving sertraline had significantly more nausea and diarrhea and significantly lowered libido. This is useful information for patients who are prescribed sertraline regularly.

Analysis of methodology

Overall, investigators conducted a well-designed trial. Unlike many other authors investigating serotonin reuptake inhibitors (SSRIs) in PMDD, these investigators used validated instruments to measure symptoms and functional outcomes. The placebo run-in phase was valuable for differentiating true therapeutic response. Compliance was assessed by pill counts at each visit. Reasons patients dropped out were explicitly stated for each phase of the trial, and patients were appropriately accounted for throughout the trial.

Limitations of the trial include the fact that dose titration of sertraline was left to the discretion of each investigator rather than being set by more objective criteria. Interrater reliability scoring to show consistency of evaluation among various investigators was not performed. Also, investigators evaluated only the short-term (3 months) efficacy and safety of sertraline for PMDD. Long-term outcomes were not addressed.

Application to clinical practice

Certainly, nonpharmacologic approaches to managing symptoms can be tried first (diet, exercise), especially for patients with mild PMS symptoms. Psychological interventions, such as support groups and stress management, are usually helpful. Although sertraline had statistically significant results over placebo in most end points studied, it is difficult to ascertain whether these differences are truly clinically significant. Also, because head-to-head trials of other SSRIs have not been held to seek the outcomes evaluated in this trial, we cannot conclude with certainty that the benefits seen with sertraline represent an SSRI class effect.

Several issues limit generalizability of the data from this trial to the general population of women seen by family physicians. The trial did not involve women with concurrent psychiatric illnesses or women with less severe PMS symptoms; it involved patients referred from specialty psychiatric clinics and gynecology departments. The trial was performed in an environment in which compliance was intensely monitored and among women who were willing to keep regular appointments and record daily symptoms. All these factors could have contributed to a positive therapeutic response.

It is often difficult for nonexperts to judge what a few points’ difference in a cognitive-behavioural scale means clinically. For this reason, it was helpful to add the Social Adjustment Scale to indicate how depressive illness affects lifestyle and coping. The improvement in patients’ ratings and function was useful for obtaining patient-oriented evidence.

The advantages of SSRIs over other proposed PMDD therapies include a favourable side-effect profile, ease of administration (once daily dosing), and relative safety in overdose. Questions addressing appropriate duration of therapy and long-term efficacy and safety, however, await further study.

Bottom line

Sertraline appears to be well tolerated and effective for improving the symptoms and reducing the functional impairment associated with PMDD. It can be considered an effective therapeutic alternative for treating PMDD. Long-term efficacy and safety remain uncertain.

1981

The first modern antidepressant drugs were developed in the 1950s. Initially drugs which were inhibitors of the enzyme monoamine oxidase (MAO) were discovered to have useful antidepressant properties and, several years later, a second and more important class of antidepressant compounds was discovered. Imipramine is the prototype of the latter category, known as the tricyclic antidepressants (TAD) and now much more extensively used than the MAO inhibitors. Through the years, an ever-increasing number of TADs has become available; however, most of the new drugs are analogues of existing compounds rather than completely new chemical entities. At this time three MAO inhibitors and ten TADs and related compounds are marketed in Canada, while several others are under investigation. Antidepressants marketed in Canada are listed in Table 1 by generic name and principal trademark; the optimum daily dosage range for office patients is also given. The introduction of each new antidepressant is accompanied by claims of advantages which are usually expressed in terms of a more rapid onset of action, less severe side effects and lower toxicity, especially cardiotoxicity. Although in clinical use these claims are often very difficult to evaluate, the many drugs available do allow selectivity in matching the pharmacological profile of an antidepressant with a patient’s condition and needs.

When to Use Antidepressants

Depression is a very frequent illness with a much higher prevalence in the community than indicated by the number of diagnosed and treated cases. Family doctors are likely to see depressions of less severe intensity and in an earlier phase of their course than psychiatrists. Since many such office patients present ‘masked depressions’ or ‘depressive equivalents’ where somatic symptoms overshadow the affective disturbance, the differential diagnosis of depression should be considered when certain patterns of physical symptoms are present, diagnostic investigation reveals no physical cause and symptomatic relief is not obtained with the usual remedies. The symptom complexes of anxiety, fatigue, chronic pain syndrome or gastrointestinal disturbances are the most frequent physical concomitants of an underlying depression.

A trial of treatment with antidepressants is indicated under the following circumstances: when the depression has lasted more than one or two weeks; when the patient’s sense of wellbeing and ability to perform to his usual level in customary family, social and vocational roles are impaired; when psychotherapy or treatment with sedatives, anti-anxiety agents or stimulants has not provided relief. Although depression is frequently associated with environmental stress, the presence of such stress does not preclude chemotherapy. Likewise, antidepressant chemotherapy and psychotherapy are mutually reinforcing and should be used jointly.

Clinical Pharmacology

Quickly absorbed after oral ingestion, TADs are highly lipid-soluble drugs, extensively metabolized by the liver and bound to the tissues, where their concentration is 10-20 times higher than in the blood. The essential effect of tricyclic metabolism is to form water-soluble compounds readily excreted in the urine. Tertiary amines like amitriptyline and imipramine are demethylated to secondary amines, nortriptyline and desipramine respectively, which retain clinical activity.

Blood Levels

People treated with identical doses of TAD develop markedly different blood levels of the drug. Since the blood concentration is more closely related to the biological action of the TAD than to the dose, it is possible to adjust the dose of a TAD until levels within a defined therapeutic range are attained.

Monitoring blood levels of TAD has been found clinically useful as therapeutic ranges have been established for several of these agents (Table 2). In general, the interpretation of blood level data is rather complex.

Metabolic Tests

Recently, it has been proposed that response to a specific antidepressant might be predicted by an initially high or low urinary excretion of MHPG, a norepinephrine metabolite. There is stronger evidence that the accuracy of diagnosis may be improved by using the dexamethasone suppression test. However, these are as yet experimental techniques and not applied routinely in clinical practice.

Which Antidepressant?

When starting treatment, the initial choice almost inevitably falls upon one of the TAD or related compounds. The use of MAO inhibitors is considerably restricted by their potential for serious side effects resulting from interactions with other drugs, foods and beverages. Although the risks associated with the MAO inhibitors have been overstated, the tricyclics are generally safer, more effective and thus more versatile.

There is no clearly evident overall superiority of one tricyclic over the others and in most patients therapeutically equivalent doses of different TADs will likely produce equal clinical results. In other words, amitriptyline and protriptyline are equally efficacious, but the latter is five times more potent on a milligram basis (see Table 1).

Imipramine and amitriptyline are the standard by which the other TADs are measured. Desipramine and nortriptyline are their respective active metabolites; a more rapid onset of action has been claimed but not always seen. Amitriptyline has the strongest anticholinergic action of the TADs and desipramine the weakest, with the other compounds in an intermediate position. Protriptyline and desipramine have the most pronounced stimulant action. Doxepin appears to be somewhat less cardiotoxic than the other TADs; along with trimipramine, its antidepressant effect does not appear to be as powerful as that of the earlier compounds. Maprotiline has a novel tetracyclic structure but is otherwise comparable to the other secondary amines. Amoxapine, the newest product, requires higher dosage than the others and has a structural affinity to the antipsychotic drug loxapine. Clomipramine has been found to have a therapeutic effect on obsessive-compulsive disorders apparently independent of its antidepressant action.

In general, patients incur the lowest costs if older preparations are prescribed generically, in the highest strength tablet compatible with the dosage schedule.

Clinical Use

A particular antidepressant should be selected on the basis of the physician’s personal experience with the consistent use of several of these drugs. The relative chances for various side effects with the different drugs should also be weighed. The labels affixed to depression such as reactive, endogenous, neurotic, psychotic, masked, etc., should not be relied upon for guidance in selecting a drug. Factors such as the physician’s experience with one or the other drug, the patient’s age and cardiac status, and personal or family history of response to previous antidepressant treatment are much more important. If the patient or a blood relative has responded favorably to a given antidepressant, the same agent should be used again.

Before starting treatment it is usually not necessary to perform a complex medical examination in younger and healthy individuals. Elderly depressed patients are at much greater risk of toxic effects and with such patients the status of the cardiovascular, cerebrovascular, urinary and ophthalmologic systems should be established. While TADs are not recommended for children under 12 years, imipramine in a bedtime dose of 25-75 mg has been used in young children to treat enuresis and school phobias.

Principles of Dosage

Some TADs are available in inject-able forms, but these are rarely used. A typical oral daily starting dose for a healthy adult might be 50-75 mg imipramine (or equivalent) prescribed as 25 mg bid or tid. The amount is usually increased by 25 or 50 mg every day until a dose of 100-200 mg a day is attained. Dose increments are prescribed according to the patient’s tolerance of the medication, incidence and severity of side effects and clinical response. Doses above 200 mg a day of imipramine (or equivalent) are associated with an increased risk of toxi-city and are best reserved for carefully supervised hospital patients.

The timing of doses through the day is important. Maximum doses should be achieved gradually. Since the half-lives of the antidepressants are sufficiently long, sustained-release formulations usually confer no special advantage. It is preferable to use the bulk of the daily dose at bedtime for convenience, to improve compliance and to exploit any sedative effect. When initiating treatment or when large doses of an antidepressant are used, divided doses should be used to minimize the anticholinergic and cardiotoxic actions of these drugs.

Because all the antidepressants have a limited margin of safety, it is unwise to dispense more than a week’s supply to a depressed and possibly suicidal outpatient. Suicide risk should be assessed and noted for each patient. Patients’ family members should be asked to help supervise the drug treatment. The drug should be kept out of the reach of children and in a securely closed container.

As far as possible, antidepressants should be the only drug administered to a patient, both in the interest of reducing the burden of chemical toxicity and to evaluate treatment response without having to consider the interactional influence of other medications. If it is necessary to control anxiety or insomnia, use of a benzodiazepine (diazepam, lorazepam, flurazepam, nitrazepam, etc.) is preferable.

How Long to Treat?

With all antidepressants there may be a delay in the onset of antidepressant effect, typically at least a week and sometimes up to three or four weeks. However, in many patients, objective signs of improvement may be observable within the first week— although the patient may be the last to acknowledge this. If no improvement is evident after three or four weeks and a full therapeutic dose has been reached, there is little likelihood that changing to another tricyclic or further increasing the dose will help. Since the main alternatives are then to try an MAO inhibitor or ECT, or to review the diagnosis, referral to a specialist is opportune.

Concerning duration of treatment, it is appropriate to continue at 100-150 mg of imipramine (or equivalent) for at least three months and then to decrease the dose gradually by 25 mg or 50 mg each week while observing for the possible breakthrough of depressive symptoms. In severe depression or in patients with a prior history of frequently recurring depression it is best to continue the treatment for a year or more. Although antidepressants have been administered for several years for the prophylaxis of recurrent depressions without apparent ill-effects, the efficacy and safety of indefinitely prolonged antidepressant therapy are not fully established. Lithium prophylaxis has been reported to be as successful in preventing depressive recurrences as longterm treatment with imipramine.

Side Effects and Toxicity

There is a low margin of safety between therapeutic and toxic doses of TADs. The most common side effects are extensions of the TAD’s pharma-cologic activities, foremost among which is the anticholinergic action responsible for the symptoms of dry mouth, sweating and impaired accommodation. These problems are usually more annoying than dangerous and can be managed by simple means such as mouthwashes or reading glasses. Some degree of tolerance to the side effects usually develops.

Among the more serious effects are the induction of glaucoma, paralytic ileus and urinary retention. Extra caution is thus required in elderly patients and men with hypertrophy of the prostate. Cardiac toxicity is a serious consequence of the anticholinergic and quinidine-like properties of the TAD and is to be expected in cases of acute over dosage or in sensitive individuals. Antidepressants must be used in lower doses and with great caution in elderly persons at risk for myocardial infarction and stroke. ECT modified by general anesthesia and muscle relaxation is as safe or safer than antidepressants for the treatment of severe depressions in the elderly or infirm.

The untoward CNS effects range from restlessness or insomnia to a toxic organic psychosis resembling atropine poisoning. Since TADs lower the seizure threshold, increased doses of anticonvulsants may be required.

The tricyclic antidepressants are a common choice for overdose. Acute doses of a few hundred mg of imipramine (or equivalent) have been severely toxic in adults as well as in children. Acute doses above 1000 mg are almost invariably very toxic and acute doses in excess of 2000 mg are often fatal. TADs pass the placental barrier and if used in pregnancy the balance of potential risk and benefit must be carefully weighed. In lactation, levels of antidepressants reaching breast milk and the infant’s plasma are minute, but cessation of breast-feeding is recommended.

Antidepressants and Antihypertensives

It is difficult to manage depression and hypertension in the same patient because of drug interactions. Depression may be associated with the use of several antihypertensive agents, notably reserpine and alphamethyldopa (Aldomet). Guanethidine (Ismelin) should not be used with any of the TADs, which nullify its antihypertensive action by blocking guanethidine uptake into the post-ganglionic sympathetic nerve fibers. Diuretics, beta blockers or smooth-muscle relaxants may be used with TADs.

Résumé

(French Language)

La dépression est une maladie paralysante qui n’est pas toujours diagnostiquée ni traitée. Les antidépresseurs sont un traitement spécifique pour cette condition mais leur utilisation demande beaucoup de jugement, de savoir et d’habilité. De nombreux médicaments sont disponibles mais à part quelques exceptions, à doses égales, il n’existe pas de différence substantielle dans leur efficacité totale. Le médecin se sert de son jugement clinique pour en recommander un plus que l’autre. De toute façon, les médecins doivent devenir complètement familiers avec plusieurs de ces agents. Un traitement d’essai demande des doses thérapeutiques durant trois à quatre semaines au moins. Ces médicaments ont une faible marge de sécurité; il y a du dager spécialement pour les gens âgés à cause des effets secondaires cardiaques, anticholinergiques et neurologiques. On décide empiriquement de la durée du traitement. Traiter avec succès une dépression par chimiothérapie est une des expériences les plus gratifiantes en médecine.

Treating clinical depression in pregnant and breastfeeding mothers has always required assessing the risk of using a psychotropic medication, which might affect a developing fetus, against the benefits of preventing a mother from becoming incapacitated with depressive symptoms. Increasing experience with the selective serotonin reuptake inhibitor (SSRI) class of antidepressants (eg, fluoxetine [eg, Prozac], sertraline [Zoloft], fluvoxamine [eg, Luvox], and paroxetine [Paxil]) in the peripartum period has made them a feasible option for treating depression during pregnancy and breastfeeding.

This article summarizes current information on using SSRIs during pregnancy and lactation and provides guidelines for physicians, based on the available evidence, to optimize treatment.

Quality of evidence

An extensive literature search over the last 9 years pertaining to use of SSRIs during pregnancy and breastfeeding was conducted using MEDLINE’s Ovid database. MeSH words used included selective serotonin reuptake inhibitors, antidepressants, pregnancy, lactation, teratogenicity, and “neurobehaviour.”

All articles used in this update were written in English. The update is based on information from scientific, case study, and review articles, looking specifically at each of the SSRIs and their effects on infants during pregnancy and breastfeeding.

There is little conclusive evidence on the effects of SSRI exposure on developing children during gestation and breastfeeding. Detailed information is available, however, on the effects of untreated depression during pregnancy and the postpartum period on mothers, children, and mother-infant relationships. Synthesis of these two topics suggests that SSRIs could be a treatment option for women suffering from depression during pregnancy and postpartum.

Evolution of depression in pregnancy

As clinical depression evolves, gradual changes in sleep patterns, eating habits, energy level, and concentration slowly start to have a serious effect on progression of pregnancy. Such essential things as managing self-care and maintaining adequate health through regular sleep and eating affect both mothers and developing fetuses. Darkening of mood, social withdrawal, and anhedonia influence the quality of the interaction between women and their families, partners, and social supports. Finally, accumulating feelings of poor self-esteem, hopelessness, and helplessness will make women perceive events and situations as overwhelming, and these feelings could lead to thoughts of self-harm or suicide.

Depression can precede a pregnancy, begin in the 9 months leading up to delivery, or occur postpartum. Women most at risk for developing depression have a psychiatric history of recurrent depressive episodes or prior postpartum depression. The more severe and debilitating the depression, the more important it is to monitor closely for the first signs of an evolving change of mood and to consider prophylactic use of an antidepressant during the pregnancy. If at conception, a woman is just recently recovering from a major depression that required antidepressants, it is crucial that she continue these medications because she is at extremely high risk of relapse. More than 50% of women who discontinue antidepressants need them again later in the pregnancy because of a resurgence of depressive symptoms.

Failing to initiate treatment can lead to progressively worsening depression that greatly compromises maternal-fetal health and can impair bonding and child care in the postpartum period. Studies have found that the children of mothers with untreated postpartum depression are delayed in motor development, have lower intelligence quotients (IQs), and have slower rates of growth when compared with children of mothers whose depression has been successfully treated.

The implications of untreated depression during pregnancy and postpartum are so serious that treatment of depression is essential. The vast amount of available research on treating depression during pregnancy and postpartum has focused on the efficacy of antidepressants rather than on other treatments, such as cognitive-behavioral therapy. We present evidence on use of SSRIs to help guide physicians on whether to prescribe any of the SSRIs during pregnancy and the postpartum period.

The most-studied SSRI with respect to its use in pregnancy and breastfeeding is fluoxetine. No study has found increased rates of major fetal malformations or miscarriages among women treated with fluoxetine when compared with women exposed to tricyclic antidepressants or nonteratogens, or historic outcomes reported in surveys of newborns. In the only study comparing first-trimester and third-trimester exposure, an association was found between first-trimester exposure to fluoxetine and increased incidence of three or more minor anomalies, although the nature of these anomalies was not specified.

Fluoxetine use during pregnancy can increase perinatal complications, such as premature delivery, neonatal intensive care unit admissions, poor neonatal adaptation, respiratory difficulty in infants, cyanosis on feeding, jitteriness, lower birth weight, and shorter birth length. Evidence also suggests that these perinatal complications are associated with third-trimester exposure to fluoxetine. Unfortunately, it cannot be established whether these perinatal complications are wholly or partly due to concomitant use of other psychotropic medications, to alcohol and tobacco consumption, or to degree of severity of depressive symptoms (ie, less weight gain in babies of depressed mothers could be because of the neurovegetative symptom of decreased appetite).

One long-term follow-up study investigating the effect of fluoxetine on fetuses exposed to the drug in utero assessed children up to 86 months old. These children showed no increase in negative effects, compared with unexposed children, with respect to IQ, language, temperament, mood, arousability, activity level, distractibility, or other neurobehavioral-al areas. In contrast, a substantial effect on the development of children of untreated depressed mothers has been shown.

Fluoxetine is present in breast milk at less than 10% of the adult therapeutic dose. Researchers have been able to detect both fluoxetine and its main metabolite, norfluoxetine, in the serum of exposed babies. Two case reports of nursing babies exposed to milk from mothers taking fluoxetine report increased irritability, colic, increased crying, decreased sleep, increased vomiting, and watery stools. Another case report found substantial concentrations of both fluoxetine and norfluoxetine in infants’ serum and reports of seizurelike activity.

The only published study that has assessed infants exposed to fluoxetine through breastfeeding at a 1-year follow-up examination reported no neurologic or developmental abnormalities. Taken together, these studies cannot directly relate fluoxetine exposure through breast milk to toxicity in infants, but more study is required because only 11 children have been reported on to date.

Sertraline

Case studies of the effects of sertraline on infants exposed in utero report contradictory findings. One case describes a woman who was treated throughout her pregnancy with 200 mg of sertraline. When the medication was stopped in the postpartum period, the infant exhibited signs of withdrawal that included crying, agitation, and restlessness. In a similar case report, however, no such behavioral changes were observed.

Case report data included evidence from one prospective, controlled multicentre study on women counseled during pregnancy after exposure to either fluvoxamine, paroxetine, or sertraline. These women were compared with women counseled after exposure to nonteratogenic agents. Of the 267 women studied, 147 used sertraline at an average dose of 50mg/d. The authors found no differences between the three drug treatment groups and the control group with respect to rate of major anatomic malformations, stillbirths, miscarriages, prematurity, mean birth weights, and gestation ages.3

There are 26 cases of infants exposed to sertraline through breastfeeding, and all find that sertraline and its main metabolite, desmethylsertraline, are present in breast milk at low levels (less than 5mg/mL). A concentration gradient exists, such that the highest concentration of the drug appears in the hindmilk 7 to 10 hours after maternal dosing. This information can be used to decrease the amount of sertraline to which an infant is exposed. To date, no studies report any adverse short-term effects among infants. This finding does not suggest, however, that chronic exposure to sertraline will not affect the long-term neurobehavioural development of exposed infants, a topic that has not been investigated thus far.

Paroxetine and fluvoxamine

Pregnancy outcome and perinatal effects of paroxetine and fluvoxamine have been investigated in one study. Of the 267 women taking SSRIs in this study, 97 took paroxetine (at an average dose of 30mg/d) and 26 took fluvoxamine (at an average dose of 50 mg/d). When compared with a control group exposed to nonteratogenic agents during pregnancy, the women taking paroxetine did not have an increased risk of major anatomic malformations; higher rates of miscarriage, stillbirths or prematurity; or differences in birth weight or gestational age. In addition to this study, one case report assessed neonatal withdrawal syndrome after maternal use of paroxetine during the third trimester.

Limitations

The number of studies published within the past 9 years is small. Apart from one study of the long-term developmental outcomes of infants exposed to SSRIs during pregnancy, all studies report short-term effects. In addition, most studies are single case reports that are limited in their generalizability. Without long-term and larger studies, effects of SSRI exposure on infants’ neurotransmitter systems remain unknown.31 Thus, implications derived from these studies are limited. As is true for every drug, determining the fetal safety of SSRIs cannot be ethically tested in clinical trials. It is unethical to test drugs during human pregnancy. Therefore, research proceeds safely and slowly through investigation of cases in which women conceived while taking SSRIs. For treatment clarity, investigation into the safety of SSRIs must answer some more questions. Table 1 lists areas for future research necessary to increase our understanding of the effects of SSRIs during pregnancy and lactation.

Clinical implications

During pregnancy and breastfeeding, SSRIs should be prescribed when the risk of a depressive episode is greater than the risk of taking the medication. It is strongly recommended that infants be exposed to the minimum amount of medication while still ensuring maternal mental health. Table 2 provides guidelines for physicians prescribing SSRIs during their patients’ pregnancies and lactation.

The US Food and Drug Administration puts fluoxetine, sertraline, and paroxetine in Category B and fluvoxamine in Category C. Fluoxetine could be the best choice; it is the most studied; there have been no reports of increased short-term risk to infants; and it is the only SSRI that has been evaluated, and positive results found, in terms of long-term neurodevelopmental effects. Recent information suggests that first-trimester exposure is not associated with increased risk to a developing infant, contradictory to earlier belief. Further research is required to settle this controversy.

Neonatal withdrawal syndrome is repeatedly reported with late-trimester use of fluoxetine, sertraline, and paroxetine. Therefore, the dose of the drug should be reduced before delivery to decrease withdrawal symptoms in infants. On the positive side, to date, no studies report an increase in major anatomic abnormalities or miscarriages because of SSRI use during pregnancy, regardless of trimester or length of exposure. Selective serotonin reuptake inhibitors pass through the placental barrier and infiltrate breast milk and are consequently passed on to infants. Research thus far shows that use of SSRIs during breastfeeding appears to be safe for newborns who seem to attain their early developmental milestones.

Key points

• The literature on the safety of the SSRI antidepressants fluoxetine (eg, Prozac), sertraline (Zoloft), fluvoxamine (eg, Luvox), and paroxetine (Paxil) is limited: mostly case reports and a few prospective studies. Fluoxetine is studied most.

• No studies show an increase in major congenital malformations in infants whose mothers take SSRIs.

• Infants whose mothers take high doses in the third trimester could have some withdrawal symptoms.

• Breastfeeding among mothers taking SSRIs does not seem to be associated with serious problems.

• Women suffering from serious depression, who are not treated during pregnancy or breastfeeding, put themselves and their infants at risk.

Résumé

(French Language)

Objectif

Présenter une synthèse des ouvrages scientifiques sur le recours à des antidépresseurs de la catégorie des inhibiteurs spécifiques du recaptage de la sérotonine (ISRS) chez les femmes enceintes et qui allaitent.

Source des données et sélection des études

Une recension a été effectuée dans MEDLINE sur une période couvrant les neuf dernières années. La présente étude inclut une analyse des ouvrages publiés au cours des huit dernières années. Les études principales comportent des investigations prospectives et des études de cas. Les données probantes appuyant l’innocuité des ISRS sont limitées, mais certaines études fiables décrivent les effets de dépressions non traitées.

Synthèse

Toutes les études rapportent une exposition chez les nourrissons aux ISRS; la présence du médicament peut être mesurée dans leur plasma et leur urine. Certaines données probantes font valoir une hausse des complications périnatales mineures chez les nourrissons exposés aux ISRS en fin de gestation ou pendant l’allaitement. Par ailleurs, aucune étude n’a constaté une hausse des malformations fœtales majeures ou des complications associées à la grossesse. La seule étude sur l’évolution neurologique n’a relevé aucune répercussion défavorable chez ceux qui avaient été exposés aux ISRS durant la grossesse. Les données se font rares et les lecteurs sont mis en garde de prendre en compte la nature limitée des études passées en revue avant de prendre des décisions thérapeutiques précises.

Conclusions

Les malformations fœtales majeures et l’exposition aux ISRS durant la grossesse et l’allaitement ne semblent pas associées. Certaines complications périnatales mineures ont été rapportées. Les données sur les répercussions à long terme sur le développement des enfants exposés aux ISRS in utero et durant l’allaitement sont limitées.

Points de repère

• Les ouvrages scientifiques sur l’innocuité des antidépresseurs de la catégorie des inhibiteurs spécifiques du recaptage de la sérotonine (ISRS), comme la fluoxétine (p. ex. Prozac), la sertraline (Zoloft), la fluvoxamine (Luxor) et la paroxétine (Paxil) sont limités (principalement des rapports de cas et quelques études prospectives). La fluoxétine a fait l’objet d’un plus grand nombre d’études.

• Aucune étude ne fait valoir de hausse dans les malformations congénitales majeures chez les nourrissons dont les mères prennent des ISRS.

• Les nourrissons dont les mères prennent de fortes doses durant le troisième trimestre pourraient avoir des symptômes de sevrage.

• L’allaitement par des mères qui prennent des ISRS ne semble pas associé à des problèmes sérieux.

• Les femmes qui souffrent de dépression grave, qui ne sont pas traitées durant la grossesse ou l’allaitement, prennent un risque pour elles-mêmes ainsi que pour leur nourrisson.

Though panic disorder and panic disorder with agoraphobia or phobic avoidance (PDA) are common (the mean lifetime prevalence of panic disorder is 1.5%), the diagnosis is frequently missed: 70% of patients with PDA in one large study had more than ten medical consultations before receiving the correct diagnosis and treatment.

The “classic” presentation of panic disorder consists of sudden, unexpected, discrete attacks of intense fear or discomfort without a recognizable precipitant, accompanied by at least four of the following symptoms during at least one of the attacks: dyspnea or smothering sensations; dizziness, unsteadiness, or faintness; palpitations or tachycardia; trembling or shaking; sweating; choking; nausea or abdominal distress; depersonalization or derealization; numbness or paresthesias; flushes or chills; chest pain or discomfort; fear of dying; and fear of going crazy or doing something uncontrolled. Panic disorder, however, frequently occurs with symptoms referable to only a single organ system. Such single system presentations include chest pain and dyspnea (33% to 59% of patients seen because of chest pain but with no abnormalities found on coronary angiography were found in three different studies to have PDA); balance disorder (”dizziness”) without true vertigo (25% to 50% of patients seen because of vestibular disorder symptoms have a subtype of panic disorder); abdominal discomfort, pain, and diarrhea (about 33% of patients seen by gastroenterologists were found to have PDA).

Large-scale clinical studies have shown that for most patients, PDA is a chronic relapsing disorder. Multiple family and twin studies show that panic disorder has a highly familial transmission with a strong genetic component (31% monozygotic concordance, 0% dizygotic concordance).

Panic disorder with agoraphobia has a startlingly high comorbidity and mortality. Patients with untreated PDA attempt suicide at a rate equivalent to that of patients with major depression (15% to 20% of patients). This disorder has a dramatically high incidence of comorbid major depression, alcohol abuse, substance abuse, other anxiety disorders, multiple phobias or agoraphobia, cardiovascular disease, and personality disorders. Patients with PDA experience substantially more impairment in social, family, and occupational functioning than the general population.

The proven standard of effective treatment for PDA continues to be pharmacotherapy to stop and prevent recurrent panic attacks, plus behavior therapy (exposure in vivo) for any phobic avoidance that may remain once the panic attacks have been stopped. Most clinical studies have found the first-generation tricyclic antidepressants, the monoamine oxidase inhibitors, and two of the benzodiazepines (alprazolam [Xanax] and clonazepam [Klonopin]) highly effective in stopping and preventing recurrent panic attacks when maintained at therapeutic blood concentrations. Of the newer antidepressant medications, fluoxetine (Prozac) and clomipramine hydrochloride (Anafranil) have demonstrated efficacy in PDA, whereas buproprion hydrochloride (Wellbutrin) and the nonbenzodiazepine anxiolytic buspirone hydrochloride (BuSpar) have not.

The goal of appropriate pharmacologic management is the complete absence of all panic and subpanic attacks. This can be achieved with a single medication in more than 85% of patients, though it may take several treatment trials to find the best medication. Refractory cases may require more complicated protocols.

Recent reports of two nonpharmacologic treatments, cognitive therapy and cognitive-behavioral therapy, show promise for some patients with PDA.

The core of cognitive-behavioral treatment is systematic structured exposure to the feared internal sensations, coupled with cognitive procedures to restructure anxiety-provoking thoughts, catastrophic misinterpretations, and faulty core beliefs. The therapist directs the patient to induce the somatic sensations typical of a panic attack (dizziness, tachycardia, dyspnea, chest tension) in the office (by having the patient spin around, run in place, hyperventilate, or contract chest muscles tightly), while together therapist and patient critically examine the symptom experience, correct the patient’s frightening and catastrophic cognitive misinterpretations of the sensations, and control the symptoms with a variety of relaxation techniques. The patient practices at home what is learned in the office and keeps a daily diary of symptoms, reflex cognitive distortions, and corrective thinking and behavior.

Reports of the nonpharmacologic treatment of PDA to date review small treatment populations and short follow-up periods. The few studies comparing the efficacy (short- and long-term) of pharmacologic and nonpharmacologic treatments suffer from a variety of conceptual and methodologic difficulties. These include a failure to differentiate patients with panic disorder from those with panic disorder and agoraphobia or those with subtypes of panic disorder, and the heterogeneity of diagnostic criteria, treatment procedures, and measures of clinical success. Thus, our present state of knowledge does not enable us to predict accurately which patients will do best with which treatment(s) or how different treatments might best be integrated.

Patients with PDA should be educated regarding the various treatment options available. The choice of treatment will depend on the training and expertise of the clinician, the availability of specialists, a patient’s sense of urgency, available resources, and the preferred type of treatment. If nonpharmacologic treatment is elected, those patients who are not completely relieved of panic attacks after an adequate treatment trial (three months), or who relapse after treatment, should receive appropriate pharmacologic therapy for panic, combined with exposure treatment of phobic avoidance.

Newer antidepressants are gradually replacing old tricyclic antidepressants because of comparable efficacy with fewer side effects and a much lower risk of death from overdose. Newer-generation antidepressants include trazodone hydrochloride, bupropion hydrochloride, and the selective serotonin reuptake inhibitors fluoxetine hydrochloride, sertraline hydrochloride, and paroxetine.

Trazodone and bupropion, unlike tricyclic antidepressants, are ineffective for panic. Anticholinergic effects-dry mouth, blurred vision, constipation, and urinary retention — and cardiovascular effects are less with the newer drugs than with tricyclic antidepressants. Weight loss can occur with bupropion and fluoxetine. Overdose lethality is rare with these newer drugs.

Newer antidepressants, like tricyclic antidepressants, show efficacy at two to six weeks, and about 50% to 70% of depressed patients obtain benefit. Patients who partially respond or do not respond may benefit from lithium or triiodothyronine augmentation or by changing to a different class of drug, such as from trazodone to serotonin reuptake inhibitors and serotonin reuptake inhibitors to bupropion.

Trazodone is highly sedating, and dose titration to the maximum tolerated dose is required in the 100-mg to 600-mg at bedtime range based on daytime sedation. Trazodone, 50 mg to 100 mg, is widely used as a hypnotic in lieu of potentially addicting medications. It may worsen preexisting ventricular arrhythmias. It causes priapism in about 1 in 7,000 men.

Bupropion is highly activating, may benefit adults with attention deficit disorder, and has the advantage among antidepressants of causing no sexual dysfunction. It has the disadvantage, however, of a higher seizure risk than tricyclic antidepressants. Patients with eating disorders, head trauma, seizure history, or who are taking other drugs that lower the seizure threshold (such as theophylline) should not receive this drug. The dosage is 300 to 450 mg daily and must be divided.

Fluoxetine, the first marketed serotonin reuptake inhibitor, has now been shown to be beneficial in many conditions including depression, mixed anxiety-depression, anorexia, bulimia, panic, and obsessive-compulsive disorder. The other serotonin reuptake inhibitors, sertraline and paroxetine, will probably show a similar spectrum of action and have the advantage of a shorter half-life to allow for more rapid dose adjustment and washout in case of intolerance. Selective serotonin reuptake inhibitor antidepressants may be lethal in combination with monoamine oxidase-inhibitor antidepressants.

Both bupropion and paroxetine carry less risk of precipitating mania in patients with bipolar depression than do tricyclic antidepressants.

1994

Natural Prozac: Learning to Release Your Body’s Own Anti-Depressants.

Joel C. Robertson and Tom Monte.

215 pp.

HarperCollins Publishers, Inc., New York; HarperCollins Canada Ltd., Toronto. 1997.

ISBN 0-06-251353-2

Strengths: Clearly written and easy to understand.

Weaknesses: Downplays the role of medication in the treatment of depression, which may lead patients to delay seeking medical help or to discontinue treatment prematurely; some of the program plans are not substantiated.

Audience: Patients with mild symptoms of depression or in remission who do not require drug treatment.

Natural Prozac is a useful layperson’s guide to understanding and modifying the factors that may trigger or perpetuate mild depressive symptoms. These modifiable factors include activity level, dietary habits, lifestyle behavior as well as thoughts and emotional responses. These factors are causally linked to “chemical imbalances” of 3 main neurotransmitters in the brain: dopamine, norepinephrine and serotonin. Each neurotransmitter is responsible for various states of mental functioning. Serotonin is linked to “peace, concentration and well-being”; dopamine is responsible for “alertness, energy and aggression”; and norepinephrine is involved in “speeding up your thoughts.” Alteration in the levels of each is postulated to cause malfunction of the brain and to produce an overly passive “satiation” or an overly active “arousal.” Corresponding depressive symptoms may result when triggered by 1 or more of the modifiable risk factors. Genetic, generational or conditional and situational factors are used to explain the underlying mechanisms.

To explain the effect of neurotransmitters in an easy-to-understand way, the authors use lay terms such as “gas and brake pedals.” Some concepts may be misleading and even harmful to certain patients who require continuing drug treatment. For example, references to “ending depression — safely and permanently” and to “start[ing] to taper off medication gradually” may be taken out of context by some readers. Simple outlines of the criteria from the Diagnostic and Statistical Manual of Mental Disorders are given for self-assessment of serious or suicidal depression. Situations that may trigger symptoms are well outlined with the use of case histories.

Part of the book describes “programs for healing depression,” including very specific diets and exercises to “boost the levels” of each of the neurotransmitters. Entertainment, play-acting, writing techniques and spiritual and religious practices are recommended in the context of structured daily and weekly plans for each personality type.

The book ends with a mail-in “mood optimization survey.”

The book makes indirect references to scientific studies, but there is no formal reference list or bibliography. The cover, foreword and introduction tend to exaggerate claims of “scientific proof and the “remarkable effectiveness” of the methods for “every depression sufferer.” However, there is little or no supporting evidence to substantiate these claims.

Natural Prozac is easy to read, with simple, clear vocabulary. It may be recommended for patients who have only mild symptoms of depression or are in remission. Symptoms may be attenuated in motivated readers who can modify clearly identifiable lifestyle or personality factors. However, care and caution must be exercised in regard to those who need continuing drug therapy. The book may create a false sense of security leading those with serious or recurrent symptoms to avoid seeking medical help or to discontinue therapy prematurely.

Depression sufficient to warrant professional care affects 2% to 4% of the general population. Cassem has observed that “92% of all persons suffering from it are either treated by nonpsychiatric personnel or are not treated at all”. Tricyclic antidepressants constitute the major form of treatment of depression. They are also used to treat various other conditions, such as phobias, obsessive-compulsive disorders, enuresis, sleep disorders (e.g., narcolepsy) and depressive equivalents (e.g., chronic pain). Their quinidine-like properties may soon prompt the use of these drugs as antiarrhythmic agents.

Side effects of tricyclic antidepressants are well known; these include dry mouth, blurred vision, constipation, reduced sweating, urinary retention, tachycardia, prostatism, raised intraocular tension in narrow-angle glaucoma, and toxic atropine-like effects on the central nervous system (e.g., delirium). Mentioned less often are the withdrawal symptoms, including nausea, vomiting, diaphoresis, restlessness, insomnia, headaches, dizziness, coryza, chills, gooseflesh, weakness, fatigue, musculoskeletal pain, abdominal cramps, malaise, anxiety, irritability, electrocardiogram changes, an akathisia-like syndrome and delirium. Similar symptoms are also reported when antipsychotic agents with potent antimuscarinic effects are suddenly discontinued. These symptoms are probably due to cholinergic rebound. Antipsychotic agents inhibit the metabolism of tricyclic antidepressants, so that the plasma levels of the drugs rise. Hence, withdrawal symptoms are more likely when combinations of these drugs are abruptly discontinued.

These symptoms have been reported with the most common tricyclic antidepressants in use — imipramine, amitriptyline and doxepin. They can occur with cessation of low doses, as in the case of a 29-year-old woman whose dose of amitriptyline was being tapered after 1 year of treatment; she had insomnia, anxiety, excessive sweating and abdominal cramps for 2 nights. They can also occur after a single dose is missed during active treatment. A 28-year-old woman who was depressed had been taking doxepin (25 mg three times a day) for about 28 days; nausea, restlessness and insomnia developed when she missed a single night’s dose. These symptoms can also occur following withdrawal from an overdose. A 29-year-old woman who had received treatment for an amitriptyline overdose complained of insomnia, restlessness, nausea, vomiting, excessive sweating, abdominal cramps and tension in the back of her head, all lasting for 2 days.

These withdrawal symptoms usually last about 48 hours and then, if the tricyclic antidepressant is not reinstated, will spontaneously remit.