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Outpatient management of the depressed patient
OUTPATIENT MANAGEMENT OF THE DEPRESSED PATIENT
ABSTHACT.--Major d e p r e s s i o n is a s e r i o u s , potentially l i f e - t h r e a t e n i n g illness t h a t c a n c a u s e significant p a i n a n d suffering. It afflicts u p to 50% of p a t i e n t s w h o a r e s e e n in t h e p r i m a r y c a r e setting. H o w e v e r , it is a rem a r k a b l y t r e a t a b l e d i s o r d e r , o n c e it is r e c o g n i z e d . T h e m a i n s t a y of t r e a t m e n t is e d u c a t i o n a b o u t t h e illness, brief supportive counseling, and antidepressant medication. This m o n o g r a p h is a s y n o p s i s of a b o o k , Outpatient Management of the Depressed Patient, r e c e n t l y p u b l i s h e d o n this s u b j e c t . We f o c u s o n h o w to d i a g n o s e a n d t r e a t m a j o r d e p r e s s i o n in t h e p r i m a r y c a r e setting, in w h i c h t h e v a s t m a j o r i t y of p a t i e n t s w i t h this c o n d i tion a r e s e e n . We r e v i e w t h e c o n d i t i o n itself, h o w to e s t a b l i s h t h e diagnosis, w h a t e d u c a t i o n a n d b r i e f supportlve c o u n s e l i n g a r e n e e d e d a n d h o w to p r o v i d e t h e m , h o w to s e l e c t a n a n t i d e p r e s s a n t , a n d h o w to u s e t h e d r u g to i n d u c e a n d m a i n t a i n r e m i s s i o n .
IN B R I E F This m o n o g r a p h is a synopsis of a recently published book, Outpatient Management of the Depressed Patient. Like the book, it is geared to provide a no-nonsense explanation of h o w to diagnosis and treat major depression. Major depression is a serious, potentially life-threatening illness that can cause significant pain and suffering. It affects u p to 50% of patients w h o are seen in the primary care setting. However, it is a remarkably treatable disorder, once it is recognized. More than 70% of d e p r e s s e d patients seen in the primary care setting will experience a full remission with appropriate treatment. Without effective treatment, more than 15% of patients suffering *Dr. Preskorn's book, Outpatient Management of the Depressed Patient, can be o r d e r e d through Professional Communications, Inc., at (405) 367-9838. 78
DM, February 1995
from major depression will die as a result of the condition. Death is primarily d u e to suicide but can also occur as the result of fatal accidents caused by the impairment of concentration and attention that is part of the illness. Suicide is the seventh leading cause of death in the United States for all ages a n d all groups. As m a n y as 70% of suicides are the result of major depression, which is a tragedy, given the highly treatable nature of the condition. Beyond death, depression exacts a n u m b e r of other costs on the afflicted person, the family a n d other loved ones, a n d society at large. Major depression can lead to alcohol abuse through attempts at selfmedication. It can lead to social withdrawal a n d impaired interpersonal relationships resulting from the impairment in mood, selfesteem, judgment, interest, and sex drive. These problems can cause impaired functioning in the person's role as spouse or parent, leading to marital a n d family dysfunction. Sleep disturbance, diminished energy, a n d impaired concentration/attention can cause problems in school a n d work performance, leading to the failure to advance properly in these activities. It can lead to job loss a n d financial hardship. The cost to society is e n o r m o u s in terms of the loss of productivity in the workplace and work-related injuries due to impaired concentration/attention. Despite these facts, in the vast majority of depressed patients the disorder is not diagnosed and treated. Why? One reason is that, as a result of misinformation, there is considerable stigma associated with the illness. The depressed patient may feel that he or she caused the illness or that the illness is a sign of moral weakness or of being selfindulgent. In spite of these widespread beliefs, there is no more evidence to support t h e m t h a n there was for previous widespread myths about other illnesses, s u c h as tuberculosis being due to having an artistic t e m p e r a m e n t or epilepsy being a sign of divine inspiration. These cultural m y t h s affect not only patients but also physicians. Should the depressed patient seek medical attention, the complaints are frequently dismissed as a trivial matter, or the person is given ineffective, simplistic solutions such as taking a vacation or baking a cake. Urffortunately, physicians without appropriate education are as susceptible to cultural myths as anyone else. In the past, psychiatry did not do a c o m m e n d a b l e job of teaching about psychiatric illnesses a n d their treatment. That was because until the last 10 to 20 years, psychiatry, particularly American psychiatry, was stuck in a prescientific era a n d was d o m i n a t e d by psychoanalysis, which explained all h u m a n behavior within the framework of a metaphysical theory that was essentially untestable. It was for psychiatry what other prescientific theories were for the rest of medicine. This situation limited the advancement of knowledge and care of patients, a n d we are still reaping its consequences. The failure to recognize major depression a n d the inadequate treatment of the disease are examples. DM, February 1995
79
However, psychiatry has u n d e r g o n e a quiet revolution that is slowly transforming the field. N o w psychiatric illnesses can be u n d e r s t o o d within the same model as any other medical condition. This change has b e e n m a d e possible also by improvements in our u n d e r s t a n d i n g of brain mechanisms relevant to psychopathology. The brain is the organ that is the focus of psychiatry. It is the most complicated organ in the b o d y in terms of structure and function, and it is the most difficult organ to study, being enclosed in a b o n y protective case remote from direct inspection. However, advances in neurosciences, including psychopharmacology, are permitting rapid expansion in our knowledge of brain physiology and h u m a n behavioral illnesses such as major depression. Given this n e w insight, major depression is like any other serious but treatable medical iLlness. The physician can use the same a p p r o a c h in the diagnosis and treatment of this condition as he or she w o u l d use with any other illness. The first point that should be u n d e r s t o o d is that major depression is a syndrome. It is not simply feeling sad. In fact, the m o o d complaint is not the most important complaint in terms of predicting w h o needs treatment with antidepressant medications. Instead, other signs and symptoms, specifically those involving sleep, appetite, energy, and sex drive, are more important. Major depression is not s y n o n y m o u s with being sad, and, in fact, the m o o d complaint m a y not be sadness but, rather, irritability or anxiety. Regardless of what the m o o d complaint is, it m a y not be the most prominent symptom. Particularly in older patients, the complaints m a y be more about m e m o r y problems (actually impaired concentration/attention rather than memory), sleep disturbance, or decreased energy. The important point is that the diagnosis requires a constellation of signs and s y m p t o m s b e c a u s e major depression is a syndromic diagnosis. That constellation consists of a disturbance in sleep, appetite, sex drive, concentration/attention, energy (both as subjectively experienced by the patient and as objectively observed by others), interest, and motivation, as well as a disturbance in m o o d (depression irritability, or anxiety). As with any other illness, the patient is first seen with a complaint that triggers in the physician's mind a differential diagnosis that should include the syndrome of major depression. That complaint may be quite varied. It m a y be a m o o d complaint, but often in the primary care setting it is instead a complaint about insomnia or fatigue, or a somatic complaint such as headache or backache. The physician then works through the differential diagnosis, ruling out other medical causes and ruling in major depression. To make the diagnosis, the physician must establish that the patient has the full constellation of signs and s y m p t o m s that constitute the syndrome. That can be done through a series of specific questions. Because a depressive syndrome can have medical causes other than major depression, the physician must rule out those causes. The 80
DM, February 1995
most likely ones are endocrine disorders; withdrawal of sedativehypnotic drugs, including alcohol; the use of certain types of prescribed drugs, particularly antihypertensive medications that antagonize the central actions of norepinephrine and serotonin (two neurotransmitter systems that appear to be involved in the pathophysiology of the illness); anemia; certain infections; and occult malignant diseases. Once the diagnosis is made, an appropriate treatment plan can be developed. The mainstay of treatment is education about the illness, brief supportive counseling, and antidepressant medication. The education must provide a no-nonsense, straightforward answer to the c o m m o n questions that patients have about any illness from w h i c h they are suffering. Those questions include the following: What do I have? Will I get better? What will it take to get better? What do I n e e d to do? What should I not do? Will it h a p p e n again? Do I n e e d to take treatrrient indefinitely? We provide examples of answers to these questions in an empathetic and easy-to-understand way. The next step is deciding w h e r e to treat the patient. In essence, this question is c o n c e r n e d with w h e t h e r hospitalization is needed. There are three primary reasons for hospitalization: high suicide risk, concurrent psychosis, or severity of the syndrome such that the patient cannot be managed in the h o m e environment (or more than one of these). Again, these questions can be answered through a straightforward, systematic process. The mainstay of this assessment is asking the patient specific questions and making specific observations during the mental-status examination of the patient. Examples of h o w to inquire about these issues are given in the text. In terms of evaluating suicide risk, a n u m b e r of risk factors have been elucidated through retrospective studies of persons w h o have c o m p l e t e d suicide. A m n e m o n i c is given to aid in remembering the most cogent of these risk factors. Most patients with major depression can be treated on an outpatient basis. The next question in formulating the treatment plan is UShould the patient be treated with medication?" If the patient is able (as most patients are) to make an informed decision on his or her o w n behalf, then the role of the physician is to provide an adequate explanation of the benefits and risks of treatment with antidepressant medications. For the majority of patients, the potential benefit far outweighs the potential risk. The authors' opinion is that most, ff not all, patients DM, February 1995
Sl
with a major depressive episode that has lasted at least 4 weeks deserve an empirical trial with one of the first-line antidepressants. First-line agents include selective serotonin reuptake inhibitors (SSRIs) a n d tricyclic antidepressants (TCAs). The section on the selection of an antidepressant reviews the pharmacology of these two groups as well as the pharmacology of bupropion a n d trazodone, two other types of antidepressant. Because m o n o a m i n e oxidase inhibitors are historically not prescribed by primary care physicians, their pharmacology is not reviewed. The pharmacology of these antidepressants is reviewed within the framework that leads the physician to select a medication. That framework consists of concerns about safety, efficacy, and simplicity of use. Safety concerns include the therapeutic index of the drugs (in other words, the difference between what is routinely effective and what is routinely toxic), acute and chronic tolerability, any latent safety issues that come from chronic administration, a n d any risk of pharmacokinetic a n d p h a r m a c o d y n a m i c drug interactions. The efficacy issues include the following: What percentage of patients will respond to one medication versus another? Is there any unique spectrum of antidepressant activity? In other words, are there any useful clinical or laboratory predictors of which patients will res p o n d to which medication? Also, ff patients fail to respond to one class of antidepressant medication, which class should they be treated with next? Efficacy issues also concern w h e t h e r the medication has been proven to be effective in terms of maintaining remission during the vulnerable 4 to 6 m o n t h s after the induction of a remission. It is advisable to maintain the patient on an antidepressant during this period because of the risk of a depressive relapse if medication is too quickly withdrawn. Finally, is there any evidence that the medication is effective in preventing recurrent episodes in patients w h o are at risk of such recurrences? The simplicity issue concerns w h e t h e r there is a need for dose titration to achieve the optimal dose for antidepressant response and w h e t h e r the medication can be taken once a day to improve compliance. Once an antidepressant has been selected, treatment proceeds in stages. The goal of the first stage is the induction of a remission (i.e., w h e n the patient is free of s y m p t o m s in terms of the depressive syndrome). Remission can be determined simply by the patient's selfreport or by using one of several rating scales. The Zung Depression Rating Scale is shown as an example of such a structured scale. It is one that can be readily a d a p t e d to the primary care setting because it is a form that the patient can complete in the waiting room or that can be completed with the office nurse. Remission will typically take several weeks of treatment with an antidepressant because these 82
DM, February 1995
medications have a delayed onset of antidepressant action. However, some degree of improvement is to be expected within 2 to 4 weeks and may occur even earlier in some patients. The reason for this variable time course is not fully understood. Nonetheless, knowing the time course is important for several reasons. First, the patient should be informed that there is a gradual onset of action so that he or she does not become discouraged a n d fail to comply with treatment. Second, no response after 4 weeks generally means that the physician should do something. Often it will m e a n switching from one class of antidepressant to a n o t h e r because these drugs can have different spectra of activity consistent with their apparent different mechanisms of action. Once the patient has gone into remission, he or she should be maintained on the medication for at least 4 to 6 m o n t h s in the case of a first-time episode and longer in a patient who has h a d at least one previous episode. The reason for continued treatment is that this interval is a vulnerable time for relapse into the current episode ff the medication is discontinued prematurely. Near the e n d of this interval, discontinuation of the medication should be discussed with the patient, a n d he or she should be e d u c a t e d about the early symptoms of a recurrent episode. Thus, should there be a recurrent episode, it can be identified a n d treatment can be sought before depression develops fully. This approach is analogous to early detection of any disease that has the possibility of being recurrent. After the patient has been fully e d u c a t e d about discontinuation, and assuming that he or she is agreeable, the medication should be stopped. Dep e n d i n g on the antidepressant, discontinuation may involve simply stopping the medication or it may involve a d o w n w a r d titration before complete discontinuation. Some patients will have enough recurrent episodes that they will be candidates for m a i n t e n a n c e medication to prevent recurrent episodes. The patient will usually make that decision w h e n the frequency of the episodes times their severity reaches such a critical threshold that prevention of recurrent episodes outweighs any disadvantage of having to take medication indefinitely. Generally, that decision is not m a d e until after the patient has h a d three episodes. If there is a strong family history of recurrent major depression, the decision may be m a d e sooner. The goal, then, of this m o n o g r a p h is to provide an approach to the diagnosis a n d treatment of the patient with major depression that can be readily a d a p t e d to primary care practice.
DM, February 1995
83
Sheldon H. Preskorn, MD, is a board-certified psychiatrist and fellow of the American Psychiatric Association. His medical degree is from the University o f Kansas School o f Medicine. Dr. Preskorn has undergone postgraduate medical training in pathology, as well as a rotating internship and a psychiatry residency, which was completed at Washington University in St. Louis, Missouri. Dr. Preskorn has been on the faculty o f the departments o f psychiatry at both Washington University and the University o f Kansas. He is currently professor and vice-chairman, Department of Psychiatry, University o f Kansas School o f Medicine- Wichita, and president and medical director, Psychiatric Research Institute at St. Francis Regional Medical Center in Wichita, Kansas. At the Psychiatric Research Institute, he also serves as medical director o f the lnstitute's Phase I center, which conducts first-time-into-man and pharmacokinetic research studies. Dr. Preskorn has been continuously funded for his research on psychopharmacology since 1978. His research has broadly encompassed all drug classes relevant to psychiatry; however, Dr. Preskorn's particular interest and expertise is in mood disorders such as major depression. He has been involved in the clinical trials development programs o f every antidepressant marketed in the United States in the last 10 years. His research acti~'ties in psychiatric drug development encompass the full range o f studies necessary to market a psychiatric medication from firsttime-into-man studies through clinical trials in specific patient populations. Dr. Preskorn has been a recipient of a Research Scientist Development Award for the National Institute o f Mental Health. He is the author o f more than 200 scientific and professional publications in the area o f psychopharmacology and mood disorders. He has lectured extensively in this hemisphere, Europe, and Asia and has been a consultant to various federal agencies and the pharmaceutical industry in this country and abroad. 84
DM, February 1995
Bryan Baker, RN, CCRC, is a licensed registered nurse v,~th specialty training in psychiatric nursin~ clinical psychopharmacology, and clinical drug trials research. Mr. Baker is the clinical research supervisor for the Psychiatric Research Institute in Wichita, Kansas, which is affiliated with SL Francis Regional Medical Center and the Department o f Psychiatry at the University o f Kansas School o f MedicineWichita. In this capacity, he is responsible for the day-today operation o f a research clinic focusing on new drug development f o r psychiatric and neurologic diseases. He has coordinated and been involved in more than 30 different clinical drug trials involving more than 20 different compounds, representative o f the work o f 16 major pharmaceutical companies. Mr. Baker has been involved with each o f the six most recently FDA-approved medications f o r the treatment o f depression. In addition, he has coordinated research activity involving Phase I, Phase II, and Phase III studies, as well as drug-interaction studies o f various selective antidepressants. DM, February
1995
85
ABSTHACT.--Major d e p r e s s i o n is a s e r i o u s , potentially l i f e - t h r e a t e n i n g illness t h a t c a n c a u s e significant p a i n a n d suffering. It afflicts u p to 50% of p a t i e n t s w h o a r e s e e n in t h e p r i m a r y c a r e setting. H o w e v e r , it is a rem a r k a b l y t r e a t a b l e d i s o r d e r , o n c e it is r e c o g n i z e d . T h e m a i n s t a y of t r e a t m e n t is e d u c a t i o n a b o u t t h e illness, brief supportive counseling, and antidepressant medication. This m o n o g r a p h is a s y n o p s i s of a b o o k , Outpatient Management of the Depressed Patient, r e c e n t l y p u b l i s h e d o n this s u b j e c t . We f o c u s o n h o w to d i a g n o s e a n d t r e a t m a j o r d e p r e s s i o n in t h e p r i m a r y c a r e setting, in w h i c h t h e v a s t m a j o r i t y of p a t i e n t s w i t h this c o n d i tion a r e s e e n . We r e v i e w t h e c o n d i t i o n itself, h o w to e s t a b l i s h t h e diagnosis, w h a t e d u c a t i o n a n d b r i e f supportlve c o u n s e l i n g a r e n e e d e d a n d h o w to p r o v i d e t h e m , h o w to s e l e c t a n a n t i d e p r e s s a n t , a n d h o w to u s e t h e d r u g to i n d u c e a n d m a i n t a i n r e m i s s i o n .
IN B R I E F This m o n o g r a p h is a synopsis of a recently published book, Outpatient Management of the Depressed Patient. Like the book, it is geared to provide a no-nonsense explanation of h o w to diagnosis and treat major depression. Major depression is a serious, potentially life-threatening illness that can cause significant pain and suffering. It affects u p to 50% of patients w h o are seen in the primary care setting. However, it is a remarkably treatable disorder, once it is recognized. More than 70% of d e p r e s s e d patients seen in the primary care setting will experience a full remission with appropriate treatment. Without effective treatment, more than 15% of patients suffering *Dr. Preskorn's book, Outpatient Management of the Depressed Patient, can be o r d e r e d through Professional Communications, Inc., at (405) 367-9838. 78
DM, February 1995
from major depression will die as a result of the condition. Death is primarily d u e to suicide but can also occur as the result of fatal accidents caused by the impairment of concentration and attention that is part of the illness. Suicide is the seventh leading cause of death in the United States for all ages a n d all groups. As m a n y as 70% of suicides are the result of major depression, which is a tragedy, given the highly treatable nature of the condition. Beyond death, depression exacts a n u m b e r of other costs on the afflicted person, the family a n d other loved ones, a n d society at large. Major depression can lead to alcohol abuse through attempts at selfmedication. It can lead to social withdrawal a n d impaired interpersonal relationships resulting from the impairment in mood, selfesteem, judgment, interest, and sex drive. These problems can cause impaired functioning in the person's role as spouse or parent, leading to marital a n d family dysfunction. Sleep disturbance, diminished energy, a n d impaired concentration/attention can cause problems in school a n d work performance, leading to the failure to advance properly in these activities. It can lead to job loss a n d financial hardship. The cost to society is e n o r m o u s in terms of the loss of productivity in the workplace and work-related injuries due to impaired concentration/attention. Despite these facts, in the vast majority of depressed patients the disorder is not diagnosed and treated. Why? One reason is that, as a result of misinformation, there is considerable stigma associated with the illness. The depressed patient may feel that he or she caused the illness or that the illness is a sign of moral weakness or of being selfindulgent. In spite of these widespread beliefs, there is no more evidence to support t h e m t h a n there was for previous widespread myths about other illnesses, s u c h as tuberculosis being due to having an artistic t e m p e r a m e n t or epilepsy being a sign of divine inspiration. These cultural m y t h s affect not only patients but also physicians. Should the depressed patient seek medical attention, the complaints are frequently dismissed as a trivial matter, or the person is given ineffective, simplistic solutions such as taking a vacation or baking a cake. Urffortunately, physicians without appropriate education are as susceptible to cultural myths as anyone else. In the past, psychiatry did not do a c o m m e n d a b l e job of teaching about psychiatric illnesses a n d their treatment. That was because until the last 10 to 20 years, psychiatry, particularly American psychiatry, was stuck in a prescientific era a n d was d o m i n a t e d by psychoanalysis, which explained all h u m a n behavior within the framework of a metaphysical theory that was essentially untestable. It was for psychiatry what other prescientific theories were for the rest of medicine. This situation limited the advancement of knowledge and care of patients, a n d we are still reaping its consequences. The failure to recognize major depression a n d the inadequate treatment of the disease are examples. DM, February 1995
79
However, psychiatry has u n d e r g o n e a quiet revolution that is slowly transforming the field. N o w psychiatric illnesses can be u n d e r s t o o d within the same model as any other medical condition. This change has b e e n m a d e possible also by improvements in our u n d e r s t a n d i n g of brain mechanisms relevant to psychopathology. The brain is the organ that is the focus of psychiatry. It is the most complicated organ in the b o d y in terms of structure and function, and it is the most difficult organ to study, being enclosed in a b o n y protective case remote from direct inspection. However, advances in neurosciences, including psychopharmacology, are permitting rapid expansion in our knowledge of brain physiology and h u m a n behavioral illnesses such as major depression. Given this n e w insight, major depression is like any other serious but treatable medical iLlness. The physician can use the same a p p r o a c h in the diagnosis and treatment of this condition as he or she w o u l d use with any other illness. The first point that should be u n d e r s t o o d is that major depression is a syndrome. It is not simply feeling sad. In fact, the m o o d complaint is not the most important complaint in terms of predicting w h o needs treatment with antidepressant medications. Instead, other signs and symptoms, specifically those involving sleep, appetite, energy, and sex drive, are more important. Major depression is not s y n o n y m o u s with being sad, and, in fact, the m o o d complaint m a y not be sadness but, rather, irritability or anxiety. Regardless of what the m o o d complaint is, it m a y not be the most prominent symptom. Particularly in older patients, the complaints m a y be more about m e m o r y problems (actually impaired concentration/attention rather than memory), sleep disturbance, or decreased energy. The important point is that the diagnosis requires a constellation of signs and s y m p t o m s b e c a u s e major depression is a syndromic diagnosis. That constellation consists of a disturbance in sleep, appetite, sex drive, concentration/attention, energy (both as subjectively experienced by the patient and as objectively observed by others), interest, and motivation, as well as a disturbance in m o o d (depression irritability, or anxiety). As with any other illness, the patient is first seen with a complaint that triggers in the physician's mind a differential diagnosis that should include the syndrome of major depression. That complaint may be quite varied. It m a y be a m o o d complaint, but often in the primary care setting it is instead a complaint about insomnia or fatigue, or a somatic complaint such as headache or backache. The physician then works through the differential diagnosis, ruling out other medical causes and ruling in major depression. To make the diagnosis, the physician must establish that the patient has the full constellation of signs and s y m p t o m s that constitute the syndrome. That can be done through a series of specific questions. Because a depressive syndrome can have medical causes other than major depression, the physician must rule out those causes. The 80
DM, February 1995
most likely ones are endocrine disorders; withdrawal of sedativehypnotic drugs, including alcohol; the use of certain types of prescribed drugs, particularly antihypertensive medications that antagonize the central actions of norepinephrine and serotonin (two neurotransmitter systems that appear to be involved in the pathophysiology of the illness); anemia; certain infections; and occult malignant diseases. Once the diagnosis is made, an appropriate treatment plan can be developed. The mainstay of treatment is education about the illness, brief supportive counseling, and antidepressant medication. The education must provide a no-nonsense, straightforward answer to the c o m m o n questions that patients have about any illness from w h i c h they are suffering. Those questions include the following: What do I have? Will I get better? What will it take to get better? What do I n e e d to do? What should I not do? Will it h a p p e n again? Do I n e e d to take treatrrient indefinitely? We provide examples of answers to these questions in an empathetic and easy-to-understand way. The next step is deciding w h e r e to treat the patient. In essence, this question is c o n c e r n e d with w h e t h e r hospitalization is needed. There are three primary reasons for hospitalization: high suicide risk, concurrent psychosis, or severity of the syndrome such that the patient cannot be managed in the h o m e environment (or more than one of these). Again, these questions can be answered through a straightforward, systematic process. The mainstay of this assessment is asking the patient specific questions and making specific observations during the mental-status examination of the patient. Examples of h o w to inquire about these issues are given in the text. In terms of evaluating suicide risk, a n u m b e r of risk factors have been elucidated through retrospective studies of persons w h o have c o m p l e t e d suicide. A m n e m o n i c is given to aid in remembering the most cogent of these risk factors. Most patients with major depression can be treated on an outpatient basis. The next question in formulating the treatment plan is UShould the patient be treated with medication?" If the patient is able (as most patients are) to make an informed decision on his or her o w n behalf, then the role of the physician is to provide an adequate explanation of the benefits and risks of treatment with antidepressant medications. For the majority of patients, the potential benefit far outweighs the potential risk. The authors' opinion is that most, ff not all, patients DM, February 1995
Sl
with a major depressive episode that has lasted at least 4 weeks deserve an empirical trial with one of the first-line antidepressants. First-line agents include selective serotonin reuptake inhibitors (SSRIs) a n d tricyclic antidepressants (TCAs). The section on the selection of an antidepressant reviews the pharmacology of these two groups as well as the pharmacology of bupropion a n d trazodone, two other types of antidepressant. Because m o n o a m i n e oxidase inhibitors are historically not prescribed by primary care physicians, their pharmacology is not reviewed. The pharmacology of these antidepressants is reviewed within the framework that leads the physician to select a medication. That framework consists of concerns about safety, efficacy, and simplicity of use. Safety concerns include the therapeutic index of the drugs (in other words, the difference between what is routinely effective and what is routinely toxic), acute and chronic tolerability, any latent safety issues that come from chronic administration, a n d any risk of pharmacokinetic a n d p h a r m a c o d y n a m i c drug interactions. The efficacy issues include the following: What percentage of patients will respond to one medication versus another? Is there any unique spectrum of antidepressant activity? In other words, are there any useful clinical or laboratory predictors of which patients will res p o n d to which medication? Also, ff patients fail to respond to one class of antidepressant medication, which class should they be treated with next? Efficacy issues also concern w h e t h e r the medication has been proven to be effective in terms of maintaining remission during the vulnerable 4 to 6 m o n t h s after the induction of a remission. It is advisable to maintain the patient on an antidepressant during this period because of the risk of a depressive relapse if medication is too quickly withdrawn. Finally, is there any evidence that the medication is effective in preventing recurrent episodes in patients w h o are at risk of such recurrences? The simplicity issue concerns w h e t h e r there is a need for dose titration to achieve the optimal dose for antidepressant response and w h e t h e r the medication can be taken once a day to improve compliance. Once an antidepressant has been selected, treatment proceeds in stages. The goal of the first stage is the induction of a remission (i.e., w h e n the patient is free of s y m p t o m s in terms of the depressive syndrome). Remission can be determined simply by the patient's selfreport or by using one of several rating scales. The Zung Depression Rating Scale is shown as an example of such a structured scale. It is one that can be readily a d a p t e d to the primary care setting because it is a form that the patient can complete in the waiting room or that can be completed with the office nurse. Remission will typically take several weeks of treatment with an antidepressant because these 82
DM, February 1995
medications have a delayed onset of antidepressant action. However, some degree of improvement is to be expected within 2 to 4 weeks and may occur even earlier in some patients. The reason for this variable time course is not fully understood. Nonetheless, knowing the time course is important for several reasons. First, the patient should be informed that there is a gradual onset of action so that he or she does not become discouraged a n d fail to comply with treatment. Second, no response after 4 weeks generally means that the physician should do something. Often it will m e a n switching from one class of antidepressant to a n o t h e r because these drugs can have different spectra of activity consistent with their apparent different mechanisms of action. Once the patient has gone into remission, he or she should be maintained on the medication for at least 4 to 6 m o n t h s in the case of a first-time episode and longer in a patient who has h a d at least one previous episode. The reason for continued treatment is that this interval is a vulnerable time for relapse into the current episode ff the medication is discontinued prematurely. Near the e n d of this interval, discontinuation of the medication should be discussed with the patient, a n d he or she should be e d u c a t e d about the early symptoms of a recurrent episode. Thus, should there be a recurrent episode, it can be identified a n d treatment can be sought before depression develops fully. This approach is analogous to early detection of any disease that has the possibility of being recurrent. After the patient has been fully e d u c a t e d about discontinuation, and assuming that he or she is agreeable, the medication should be stopped. Dep e n d i n g on the antidepressant, discontinuation may involve simply stopping the medication or it may involve a d o w n w a r d titration before complete discontinuation. Some patients will have enough recurrent episodes that they will be candidates for m a i n t e n a n c e medication to prevent recurrent episodes. The patient will usually make that decision w h e n the frequency of the episodes times their severity reaches such a critical threshold that prevention of recurrent episodes outweighs any disadvantage of having to take medication indefinitely. Generally, that decision is not m a d e until after the patient has h a d three episodes. If there is a strong family history of recurrent major depression, the decision may be m a d e sooner. The goal, then, of this m o n o g r a p h is to provide an approach to the diagnosis a n d treatment of the patient with major depression that can be readily a d a p t e d to primary care practice.
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Sheldon H. Preskorn, MD, is a board-certified psychiatrist and fellow of the American Psychiatric Association. His medical degree is from the University o f Kansas School o f Medicine. Dr. Preskorn has undergone postgraduate medical training in pathology, as well as a rotating internship and a psychiatry residency, which was completed at Washington University in St. Louis, Missouri. Dr. Preskorn has been on the faculty o f the departments o f psychiatry at both Washington University and the University o f Kansas. He is currently professor and vice-chairman, Department of Psychiatry, University o f Kansas School o f Medicine- Wichita, and president and medical director, Psychiatric Research Institute at St. Francis Regional Medical Center in Wichita, Kansas. At the Psychiatric Research Institute, he also serves as medical director o f the lnstitute's Phase I center, which conducts first-time-into-man and pharmacokinetic research studies. Dr. Preskorn has been continuously funded for his research on psychopharmacology since 1978. His research has broadly encompassed all drug classes relevant to psychiatry; however, Dr. Preskorn's particular interest and expertise is in mood disorders such as major depression. He has been involved in the clinical trials development programs o f every antidepressant marketed in the United States in the last 10 years. His research acti~'ties in psychiatric drug development encompass the full range o f studies necessary to market a psychiatric medication from firsttime-into-man studies through clinical trials in specific patient populations. Dr. Preskorn has been a recipient of a Research Scientist Development Award for the National Institute o f Mental Health. He is the author o f more than 200 scientific and professional publications in the area o f psychopharmacology and mood disorders. He has lectured extensively in this hemisphere, Europe, and Asia and has been a consultant to various federal agencies and the pharmaceutical industry in this country and abroad. 84
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Bryan Baker, RN, CCRC, is a licensed registered nurse v,~th specialty training in psychiatric nursin~ clinical psychopharmacology, and clinical drug trials research. Mr. Baker is the clinical research supervisor for the Psychiatric Research Institute in Wichita, Kansas, which is affiliated with SL Francis Regional Medical Center and the Department o f Psychiatry at the University o f Kansas School o f MedicineWichita. In this capacity, he is responsible for the day-today operation o f a research clinic focusing on new drug development f o r psychiatric and neurologic diseases. He has coordinated and been involved in more than 30 different clinical drug trials involving more than 20 different compounds, representative o f the work o f 16 major pharmaceutical companies. Mr. Baker has been involved with each o f the six most recently FDA-approved medications f o r the treatment o f depression. In addition, he has coordinated research activity involving Phase I, Phase II, and Phase III studies, as well as drug-interaction studies o f various selective antidepressants. DM, February
1995
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