Since the 1983 report, many of the original study subjects have experienced multiple recurrences of major depressive disorder (MDD). In a study published in the Feb. issue of The American Journal of Psychiatry, David A. Solomon, M.D., and colleagues prospectively focused on the time to recurrence of MDD across multiple episodes. They predicted that the risk of recurrence would decrease as time of recovery increased. They also predicted that each recurrence would increase the risk of a subsequent recurrence.

The original collaborative depression group had a total of 955 patients. Of those, 318 recovered from their intake episode of major depression and were at risk of recurrence during the 10-year follow-up period. The study group for the Solomon et al. analysis consisted of these 318 subjects. Recovery was defined as at least eight consecutive weeks “with either no symptoms of major depressive disorder or only one or two symptoms at a mild level of severity”. Recurrence, which could occur only after recovery from the preceding depressive episode, was defined as the reappearance of major depressive disorder (MDD) meeting the full criteria for at least two consecutive weeks, beginning with the first of these two weeks. Episodes meeting criteria for minor depression and chronic intermittent depression were not included.

For the first five years of the follow-up study, patients were assessed every six months, and annually after that, using the Longitudinal Interval Follow-Up Evaluation. The analyses encompass data for up to 520 weeks of follow-up. As an observational study, treatment was not randomized or in any way controlled by anyone connected to the study.

Of the 318 subjects, 263 (83%) were followed for at least five years, and 208 (65%) were followed for the entire 10-year period. During those 10 years, 481 recurrences were observed. The mean number of episodes of major depressive disorder (MDD) per year of follow-up was 0.21 (SD=0.24).

Once the first eight-week recovery period was completed for the 318 subjects, 202 suffered a recurrence. Of those subjects, 172 recovered and remained healthy for the following eight-week period. A second recurrence was suffered by 115 of those patients. The median time to recurrence for the first episode was 150 weeks; for the second, 83 weeks; and for the third 77 weeks. These intervals were significantly longer than the time to recurrence for subsequent recurrences.

The investigators were also interested in the probability of a well patient experiencing a recurrence during a six-month period (the patient having began that period still well). They found the mean probability for recurrence during the first six months after recovery was 20% (SD=6) across the five prospectively observed recurrences. They wrote, “This indicates that, on average, of the subjects at risk for recurrence, 20% had a recurrence in the first 6 months after the onset of recovery from the preceding depressive episode”.

They found that rate of recurrence decreased in subsequent six-month intervals. In the second six months the probability of recurrence was 19% (SD=7), in the third six months it was 15% (SD=6), in the fourth six months it was 13% (SD=3), in the fifth six months it was 11% (SD=3). In the final six months after the onset of recovery from the preceding depressive episode the probability of recurrence was 9% (SD=6).

Solomon et al. found that the risk for recurrence increased by 16% for each successive episode of major depression. The number of lifetime episodes of major depressive disorder (MDD) was significantly associated with recurrence during this 10-year follow-up period. Analysis showed that there was very little consistency in the time to recurrence within the subject group.

When the researchers looked at treatment of these subjects, they called the low level of maintenance pharmacotherapy during any of the four weeks immediately preceding any of the prospectively observed recurrences striking. Up to 47% to 50% of subjects received no pharmacotherapy during the four weeks immediately preceding the first three recurrences. One-third received no pharmacotherapy in the four weeks immediately preceding the fourth and fifth recurrences. During any of the preceding four-week periods, only 33% to 45% of subjects received at least 100 mg/d of imipramine (Tofranil) or its equivalent. Only 18% to 30% of subjects received at least 200 mg/d of imipramine or its equivalent during the same time period prior to any of the five prospectively observed recurrences.

Solomon et al. wrote that, as predicted, “as the duration of recovery increases, the risk of recurrences decreases or decays.” Also as predicted, “With each successive recurrence, the risk of a subsequent recurrence increases by 16%.” Consistency in time to recurrence, however, was highly variable among this group, indicating that time to recurrence is also highly variable for any individual.

Limitations of this study, the researchers pointed out, included the progressively smaller group size following each recurrence. They speculate that this caused the data analyses to underestimate rates of recurrence over a patient lifetime. Another limitation was the exclusion of minor or intermittent depression, causing a possible underreporting of the extent of psychopathology in the subject group. Finally, the researchers suggest that variability in treatment may have influenced the findings. Patients may have discontinued treatment following recovery, putting themselves at greater risk of recurrence. Recurrence may have caused other patients to discontinue treatment due to discouragement, putting these patients at risk for further recurrence as well. Solomon et al. found the lack of maintenance pharmacotherapy unfortunate, given its role in preventing recurrences

New York, London: The Guilford Press; 1997. 261 pp. with index

ISBN 1-57230-237-2

Anxiety is a profound human experience. Anxiety disorders are universal in human societies, although the diagnostic patterns vary over time and from one place to another. This volume describes some culturally bound anxiety syndromes, but dwells on the diagnostic categories of the Diagnostic and Statistical Manual of Mental Disorders, third (DSM-III), third revised (DSM-III-R) and fourth (DSM-IV) editions. This manual provides diagnostic criteria for panic disorder, phobias, obsessive-compulsive disorder, post-traumatic stress disorder and the generalized anxiety disorder. Twenty-seven prominent psychiatrists, psychologists and experts from related fields contributed to this volume, offering guidelines for diagnosis and culturally informed treatment.

The first part of the book deals with general issues in the cross-cultural treatment of anxiety disorders. The second part of the volume deals with the treatment of specific ethnic groups in the US, including Hispanic-, Caribbean-, Asian- and African-Americans, as well as Orthodox Jews, and Asian-Indian-Americans. The third part of the book examines the relations between psychopharmacology and ethnicity, and modern aspects of the clinical and research agenda in culture and anxiety.

P.J. Guarnaccia addresses risk factors, symptoms of distress, and the diagnosis of post-traumatic stress disorder (PTSD) among refugee groups from Southeast Asia and Central America. PTSD occurs with depressive disorders, and its prevalence rates vary in populations of trauma victims. E. Horwath and M.M. Weissman analyze epidemiological data on anxiety based on DSM-III and DSM-III-R criteria, comparing prevalence rates from the United States with data from other countries. The lifetime prevalence rates of panic disorder are remarkably consistent across community studies and ethnic boundaries. Data on agoraphobia show more variation across studies and cross-culturally.

The chapters in the second part of the book are organized around common themes. These include a description of the culture of the group, its view of mental illness and anxiety, treatment expectations, the possibilities of a therapeutic alliance and family involvement. E. Salman and colleagues examine anxiety disorders of Hispanic-Americans. The authors analyze the culturally bound syndrome of “ataque de nervios,” which is a folk label for loss of control, often with anxiety. The authors stress the need to reconcile the folk diagnoses with the DSM-IV framework.

S.-A. Gopaul-McNicol and J. Brice-Baker compare indigenous and western treatments of anxiety disorders in the Caribbean. G.Y. Iwamasa analyzes demographic and clinical variables in Asian-Americans, who tend to underuse both outpatient and inpatient mental health services. The author points out that, in many Asian ethnic groups, the needs of the family take precedence over those of the individual, that and religion and spirituality are important in everyday family life. CM. Paradis and her colleagues focus on the cognitive-behavioural treatment of anxiety disorders and emotional problems of Orthodox Jews, a minority in their own community. Confidentiality is important in this culture, and mental illness often has to be concealed. The assessment and treatment of patients with strong religious beliefs remain a mental health challenge.

There is still limited information on anxiety disorders in African-Americans. A.M. Neal-Barnett and J. Smith argue that the African-Americans have been targets of misdiagnosis. The authors discuss the clinical importance of spirituality, of the extended family and the therapeutic alliance in the treatment. R. Viswanathan and colleagues stress the fact that some attitudes of patients from the Indian subcontinent tend to be sociocentric rather than egocentric. Family and neighbours are valued, gender and hierarchical roles are rule-bound, and behaviour is influenced by the concept of shame.

In the third part of the volume, I.M. Lesser and colleagues provide a valuable overview of the clinical research on psychopharmacology and ethnicity, mechanism of drug effects and response to treatment. The authors highlight the interplay of ethnic background and genetics, but many of the important variables and relations need more research. In his closing chapter, L.J. Kirmayer reflects on the role of culture in emotional experience, considering the variations of anxiety symptoms in an increasingly ethnically diverse society.

The authors offer an updated and deep insight into factors inherent in the development, manifestation and treatment of anxiety in subjects from different cultures and ethnic groups. The book is well structured and clearly written, though the anxietynculture relations are complex and the evidence is still fragmented. This useful book will interest students and scholars in transcultural psychiatry/psychology and mental health professionals working with patients from ethnic groups.

Pies RW

Washington: American Psychiatric Press; 1998. 416 pp. with index

ISBN 0-88048-765-8

This concise, slim, well-edited paperback review of essential psychopharmacology is divided into 4 chapters, on antidepressants, anti-psychotics, anxiolytics and sedative-hypnotics, and mood stabilizers, including novel anticonvulsants. Each chapter begins with an overview that includes drug class indications, mechanism of action, pharmacokinetics, common side effects, drug interactions, augmentation strategies, and use in special populations, such as pregnant women, the elderly, and develop-mentally disabled patients. Each chapter ends with a series of well-selected, clinically relevant questions, along with answers and a case discussion that illustrate and clarify various teaching points.

The chapter on antidepressants is a general review of the literature in that area. I often hear residents expressing their concern about the inability to keep up with the number of new antidepressants being introduced into our pharmacopoeia. It is also not uncommon to meet residents who, in their final years of training, have yet to prescribe or be familiar with the frequent clinical challenges in using tricyclic antidepressants or monoamine oxidase inhibitors. This chapter provides a user-friendly review of the newer agents and also the “older” classes of antidepressants. The author succeeds in assembling the information in a way that is not information overload and yet is academically and clinically useful, particularly for residents. This is made possible in part by the author’s careful use of various tables, which compare clinical issues such as off-label indication, neurotransmitter effects, side effects and their basic management, drug-drug interactions, and therapeutic drug monitoring.

The chapter on antipsychotics provides the reader with a concise, comparative review of conventional and atypical antipsychotics. Tables illustrate comparative mechanisms of action and side effects, along with strategies for antipsychotic potentiation. This latter issue is something clinicians are often faced with, particularly in patients who cannot tolerate or respond poorly to antipsychotics, including the newer atypicals. The question section deals with disparate clinical areas, and has a very good review of neuroleptic malignant syndrome.

The chapter on sedative-hypnotics and anxiolytics has several useful charts, such as a diazepam equivalency chart, a chart of clinical indications, and a table on the off-label uses for clonidine and β-blockers.

The final chapter, on mood stabilizers, has a clinically relevant review of lithium, valproate and carbamazepine. The author has included an up-to-date review of gabapentin and lamotrigine and their potential interactions with other commonly used psychiatric medicines.

As a psychiatric educator, I was very pleased with the question-and-answer section in this book. In fact, I have yet to come across a similar psychiatric textbook that effectively asks well-selected clinically relevant questions and provides the reader with practical answers. I do like how the author began by providing the basic informational background to these various compounds, followed by questions forcing the reader to “work” the information, and rounding up with a practical case to apply this new-found knowledge.

I found the graphs, diagrams and tables very useful, and very good complements to the written material, often clarifying the concepts presented. The large print of the text is very easy to read. The information is presented in a systematic way and includes extensive references to the literature for those interested in pursuing more knowledge on the topics.

Dr. Pies’ book is intended to be a “micropedia” for residents and busy clinicians. I see it as a very useful, helpful teaching textbook and resource for its intended audience. Psychiatric psychopharmacology has had a history of being somewhat limited by the absence of clearly established evidence-based algorhythmic approaches to treatment. That being said, there have recently been useful treatment guidelines for the diagnosis and treatment of major depressive disorder, bipolar disorder, and schizophrenia, among others. The author may wish to incorporate some of these reviews in future work. Overall, I congratulate the author and recommend this text.

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.