Mingliang Zhang, Ph.D., associate director of outcomes research for Merck & Co. Inc., and his colleagues compared the costs of depression treatment provided by primary care physicians with the costs of care received from mental health specialists. They then analyzed each patient’s probable loss of earnings under each treatment method.

Referring to the estimated $12.4 billion to $19.2 billion a year spent on treating depression in the United States, the authors wrote, “Treatment costs, however, are only a small portion of the total cost to society; the consensus reached by a national panel on depression is that depression is seriously undertreated, resulting in large economic costs to society.”

The team drew its subjects from 11,078 individuals in 15,721 randomly selected households in Arkansas. The results found 998 screened positive for depressive disorder or substantial depressive symptoms. The group was further refined by eliminating subjects who exhibited suicidal ideation, those whose depression was associated with the loss of a loved one, those who had been diagnosed as having lifetime mania or those who denied all depressive symptoms during a baseline interview.

A total of 470 individuals agreed to participate in the longitudinal study, and complete medical and insurance records were obtained for 435 of them. The subjects participated in an extensive baseline interview at the beginning of the study and were interviewed again at six and 12 months. During that period, a total of 171 of the original participants received treatment for depression.

At each of the interviews, subjects were asked how many days they had worked during the previous four weeks. Based on the information provided, the researchers determined the number of hours the subjects had worked and multiplied it by each one’s hourly pay rate. Losses of jobs and changes in employment were taken into account, and gaps in wage information were filled by using the mean wage rate for each subject’s age and gender, weighted for the difference between mean earnings in Arkansas and the rest of the United States.

Medical and insurance records were analyzed to obtain data on treatments, and visits or hospitalizations for depression-related causes were isolated from general medical care. Of the 171 subjects, 56 received depression treatment from a mental health care provider, 41 of whom also received depression treatment in the general medical sector. The remaining 115 were treated for depression in the general medical sector.

Nearly half of the subjects who were treated in the mental health care sector received treatment that followed the guidelines developed by the Agency for Health Care Policy and Research, compared with only 21% of the subjects treated in the general medical sector.

Overall, the average treatment cost per patient was $1,224 higher in the mental health sector than in the general medical sector. But Zhang and his associates found that this higher cost was offset by the difference in lost earnings. They noted, “the lost earnings for the average patient receiving depression treatment in the mental health sector was $2,101 lower than that of the average patient receiving treatment in the general medical sector during the 12-month period.”

In other words, subtracting the difference in treatment cost from the difference in lost earnings, the researchers concluded that “depression treatment in the mental health sector had an overage annual net savings of $877 ($2,101-$1,224) over depression treatment in the general medical sector.”

The researchers then tested a number of scenarios, allocating some or all of the general medical visit costs to the treatment of depression, even if visits were primarily concerned with some other cause. In the base scenario, 50% of the visit cost was allocated to depression. In the first alternative scenario, 100% of the charges for a visit that included treatment for physical costs were allocated to depression. Under this scenario, the average annual net savings was $859.

Under a third scenario, with 0% of the mixed visit costs allocated to depression, the net savings for depression treatment by mental health specialists was $895. Other alternative scenarios produced similar results.

“Basically, in this case, the depression treatment cost is more than offset particularly in the mental health specialist sector compared to the general medical providers,” Zhang said in an interview.

However, Zhang declined to use the difference in results to wholly discount managed care’s benefits.

“Even in managed care, you can sometimes find good quality care,” he said. “This is not a problem of managed care per se but of how good the treatment is. If managed care tries to treat psychiatric disorders in the primary care sector-at least in the current practice standards-it seems that the employers [who sponsor managed care plans] are not reaping the greatest potential benefits.”

In their discussion, the authors noted, “Our analyses indicate that depression treatment provided by specialists, although more expensive, more than pays for itself in terms of savings in lost earnings compared with treatment provided by generalists.”

They concluded, “Although it costs less, routine treatment by generalists may not be effective enough to have an impact on patients’ functional capacity.”

Treatment of a depressive disorder must begin with a comprehensive evaluation of the older person to rule out associated medical or physical conditions that may present as depressive illness or complicate the treatment of depression. A minimum evaluation of the older depressed patient should include a careful physical examination and laboratory studies including a complete blood cell count with differential; electrolyte determination; glucose, blood urea nitrogen, calcium, phosphorous, total protein, and serum albumin levels; liver function tests; and thyroid function tests. An electrocardiogram should be obtained. Current medications, (prescribed, over-the-counter medications, and those medications borrowed from neighbors and friends) should be reviewed.

Psychopharmacologic Treatment

The psychopharmacologic treatment of depressive disorders has advanced. Pharmacologic options now include cyclic antidepressants, monamine oxidase inhibitors, and the newer serotonin reuptake-inhibiting antidepressants. The selection of a specific antidepressant is determined by the older person’s symptoms and the side effect profile of the medication. The presence or absence of sleep problems, significant complaints of decreased energy, and the presence of cognitive difficulties are important considerations in the selection of specific medications.

Additional considerations in the treatment of depression are the presence of associated medical illnesses and medications prescribed for their treatment. The choice of an antidepressant medication in this case will be based on both the side effect profile of the antidepressant and the avoidance of potential drug-drug interactions. Because of the physiologic changes of aging (decreased renal blood flow, decrease in total body water, decrease in total lean body mass, decrease in microsomal enzyme activity, and an increase in total body fat), the doses of antidepressants used in the elderly are usually one third to one half the dose prescribed in younger patients.

The approach to the titration of an antidepressant is based on the caveat of starting with a lower dose and slowly increasing it, monitoring the older person for therapeutic response, and side effects. This approach has been summarized as “starting low and going slow(ly).” In some cases, older patients will require antidepressant doses similar to persons in their 30s and 40s. Obtaining blood levels of antidepressants in nonresponding elderly, depressed patients can be helpful in determining whether to increase the prescribed antidepressant or to move to the addition of lithium carbonate to augment the antidepressant effect of the initial medication. Unless the older person has had a history of successful treatment with a monoamine oxidase inhibitor in the past, monoamine oxidase inhibitors are not the first treatment of choice. As noted earlier, electroconvulsive therapy is the treatment of choice for the delusionally depressed older patient and the cachectic, profoundly withdrawn or actively suicidal elderly patient. Although a large body of literature exists on depressive illness, further studies on the efficacy of psychopharmacologic treatment of depression, particularly in the frail, US, ethnic, minority elderly are indicated.

Psychotherapeutic Treatment

Psychological development continues throughout the life cycle. Chronological age may or may not be comparable to the person’s development age. The physician and poet, William Carlos Williams, described the older patient’s mobilization to “reach for what can be added in later life.” Gould stated that elders in contact with their inner core presented with the inevitable hazards of late life faced these developmental stressors with greater strength and were able to bounce back. Their sense of meaning resided within them and was not an external sense of meaning based on power and status. The maintenance of self-esteem may be adaptively accomplished by the elder. The psychosocial perspective of self-esteem noted that several strategies were used by older persons to defend against the erosion of their self-esteem (Table 4).

The psychotherapeutic treatment of depressive illness in the elderly should be based on the biopsychosocial model conceptualized by Engle. The therapist needs to be sensitive to the intrapsychic processes of the older person and facilitate the patient’s recognition and understanding of these psychological processes. The biological sphere has an increased effect due to the physiologic changes of aging and the associated development of physical illnesses. Clarification of the social network and social supports of the older patient as well as the various social interactions of the patient will enable the therapist to assess the extent to which the older patient is at risk to feelings of isolation or alienation. The redefinition of meaningful activity and the establishment of new goals in the context of retirement from work is an important psychological task. A successful redefinition of roles will establish new directions and goals for the older, retired individual.

Niederehe noted that psychotherapeutic intervention in the elderly was more likely to be based on psychodynamic and socioenvironmental principles. As late-life depression has been associated often with risk factors such as stressful life events, family conflict, and the absence of social resources (family support and relations with confidants), these factors partially influence the specific therapeutic intervention selected. Niederehe also noted that the significant clinical literature that existed on the value of various psychosocial treatments in the elderly were predominantly theoretical articles, description of techniques, and reports of individual treatment cases. He found few articles that met acceptable methodological standards for psychotherapy outcome research and encouraged further work in this area.

Recently published practice guidelines for major depressive disorder in adults by the American Psychiatric Association suggest specific criteria for US psychiatrists and other mental health professionals to use in the selection of a behavioral, psychodynamic, or group psychotherapy approach to the psychotherapeutic treatment of depression. Because of the potential for relapse, the continuation of antidepressant medication beyond a 9-month period of treatment will need to be discussed with the patient in the context of his or her prior history of depressive illness and response to treatment. It is recommended that the full therapeutic dose of medication that produced a therapeutic response should be continued for a minimum of 16 to 20 weeks after remission of symptoms has been achieved.

Although controversial in the US, electroconvulsive therapy is the most effective treatment for major depressive disorder. In 50% of patients nonresponsive to anti-depressants, electroconvulsive therapy has produced a satisfactory response.

Conclusion

This article reviewed the epidemiologic data on the prevalence of major depressive disorders in community resident elderly and compared international prevalence rates of depressive symptoms (4.4% to 12.6%). The prevalence rate for major depressive disorder among US residents aged 55 years and older was reported to range from 0.81 % to 1.9% among community residents and from 12% to 42% among the medically ill elderly.

Specific factors associated with a report of depressive symptoms were identified from the literature: poor physical health due to medical illness; physical disability; single marital status due to being widowed, divorced, or separated; a restricted support networks resulting in social isolation; bereavement; poverty; and education ≤4 years.

The importance of recognizing alternative presentations of depressive disorder in the elderly was emphasized. Three presentations of late-life depression were described: masked depression, pseudodementia, and delusional depression. Four types of depressive illness in the older US residents were reported by the literature: major depressive disorder, dysthymia, depressive symptoms secondary to medical illness that did not met DSM-IV criteria for a depressive disorder, and a mixed depression anxiety syndrome.

Specific concerns for the treatment of depressive disorder with psychopharmacology and psychotherapy were discussed. Antidepressant medications were needed to facilitate the biochemical readjustment of neurotransmitter levels. Psychotherapy facilitated the reactivation of prior effective, psychological coping capacities, and reworked the destructive thought patterns associated with major depressive disorder for a patient with an uncomplicated major depression. The importance of considering the social network and social roles of the elder person was emphasized. The importance of continuing an antidepressant at the full therapeutic dose for a minimum of 16 to 20 weeks after remission of symptoms was emphasized. Finally, the effective role of electroconvulsive therapy in the treatment of late-life depressive disorders was described.

Suicide

It is important to emphasize that in the US population, suicide rates are high among adolescents and higher among the elderly. Rates of completed suicide increase for white men throughout the life cycle and peak between ages 80 to 90. Rates of completed suicide by white women peak at ages 50 to 59. The divorced, white man who views his life accomplishments negatively and uses alcohol to medicate his dysphoric symptoms is the elder who completes a suicide—more usually with a firearm.

Among ethnic elders, the rates of completed suicide among Chinese-American men and Japanese-American men age 85 and older exceed the rates of white men by 20% and 60%, respectively (Table 3). The single, poor Asian male who was unable to establish a family or to bring his family to the United States because of the Asian Exclusion laws and who has isolated himself from mainstream American culture is at high risk to complete a suicide.

The ratio of suicide attempts to completed suicide in younger age US cohorts is estimated at 20:1. The ratio of suicide attempts to completed suicides in the US elderly is estimated at 4:1. Clues to suicidal ideation among the elderly include statements such as “You’d be better off without me,” behaviors of giving away prized possessions, and indefinite plans for the future. Specific questions should be asked to elicit the presence of suicidal ideation and the presence of a plan for a suicidal act. Such a direct approach will enable the older person to reveal the extent of his or her despair. Because thoughts of suicide usually are associated with fantasies of rescue, the elder may view the therapist positively and anticipate help in avoiding acting on his or her suicidal thoughts. We must remember that the elderly, while representing only 13% of the US population, complete 39% of the deaths by suicide that occur in the United States each year.

Studies summarized in the first section of this article have reported on the presence of four types of depressive disorders in the elderly. These include a major depressive disorder, dysthymic disorder, depressive symptoms associated with medical illness that do not meet the DSM-IV criteria for a major depressive disorder (termed secondary depression), and a mixed depression anxiety syndrome.

Ruegg et al described three presentations of late life depression: masked depression, pseudodementia, and delusional depression. In masked depression, the older patient presents with multiple somatic complaints such as headache, gastrointestinal upset, and fatigue. The presence of depressive symptoms is “masked” or hidden by the patient’s somatic complaints. The term “pseudodementia” describes a clinical presentation of depression that falsely mimics a dementing illness. The older person complains of difficulty concentrating or remembering, and withdraws from his or her environment. Factors facilitating the differentiation between depression and dementia are summarized in Table 2.

The third presentation of depressive disorder in the elderly is delusional depression.- After the age of 60 years, persons with a first episode of depressive illness are more likely to experience delusions. Sixty percent of all older women and 50% of all older men experience delusions. The most frequent delusions are somatic (delusion of cancer) or persecutory (being spied on), or delusions of guilt or sin. Less frequent delusions are delusions of poverty, nihilism (the world does not exist), or jealousy. Medical illnesses with symptoms mimicking a delusional depression include Binswanger’s disease, tumor, stroke, Alzheimer’s disease, and subfrontal white matter lesions. An organic personality disorder due to frontal convexity damage can produce a pseudodepression characterized by withdrawal, absence of motivation, psychomotor retardation, and a discrepancy between verbal and motor behavior. The most effective treatment for the delusion-ally depressed, older patient is electroconvulsive therapy. Electroconvulsive therapy has a significantly better outcome than the use of antidepressant and antipsychotic medications for the treatment of delusionally depressed patients.

Krishnan summarized findings from magnetic resonance imaging studies (MRI) of late-onset depressed patients. Caudate nuclear volume and metabolism were diminished. The lateral ventricles were enlarged due to leukoencephalopathy, and putamen volume was markedly diminished compared with nondepressed controls. The T1 relaxation times of the hippocampus on MRI, an indirect measure of water balance, and possible atrophy, were decreased in late-onset depressed patients compared with controls. These findings document changes in the caudate nuclei and deep frontal white matter that can affect the basal ganglia neural pathway and the limbic neuronal pathway, which are involved in mood regulation. These data suggest an organic basis for affective illness.

Description Of The Us Elderly Population

In Germany in the 1880s, Otto von Bismark defined age 65 years as the eligible age for starting social welfare benefits. In the 1930s, the US social security legislation defined persons aged 65 years as being of retirement age. When we speak of older people in the United States, we refer to the birth cohorts who are age 65 and older in the year of interest.

The population of older persons in the United States will become increasingly more culturally and racially diverse in the 21st century. The percentage of African-American and Hispanic-American elders will continue to increase. By 2040, these populations of ethnic elders combined will exceed the proportion of European-American persons age 85 and older. The old-old are the fastest growing segment of these ethnic elders. Studies to determine the presentation of psychiatric disorders and the correlation of serum levels of psychoactive medication with psychiatric symptoms among ethnic elders are another focus of needed research.

The identification of major depressive disorder in the elderly is a complex task. Because of the number of medical illnesses and the number of prescribed medications being taken, the older person may experience changes in neurovegetative signs and changes in mood as the result of their illness and medications. Affective disorders (depression and dysphoria) may present in the elderly with cognitive impairment or somatic complaints, termed “masked depression.”

In a 1972 study of a stratified random sample of Durham County, North Carolina residents aged 65 and older, 14.7% were identified by the older American Resources and Services (OARS) Depression Scale as having substantial depressive symptoms. Thirty-three percent of this sample was black. Dysphoric symptoms were found in 4.5% of these community resident elderly. Some 3.7% had symptoms of major depression, but did not meet the full criteria for a diagnosis of depression. Only 1.8% met criteria for a diagnosis of major depression, and 1.9% had a secondary depressive disorder. Community residents with secondary depressive disorder who met the criteria for a diagnosis of depression had significant dysphoric symptoms and had evidence of cognitive dysfunction or a thought disorder. Only 1% of these older, depressed community residents was receiving therapy from a trained counselor. Factors associated with depression in this sample included being white and widowed, having impairment in social economic resources, having a history of alcohol abuse more often than nondepressed community residents, and having a greater tendency to use pain medications. Of the 14.7% of the sample with depressive symptoms, 44% had impaired physical health.

In a later survey of community residents age 55 and older completed in Kentucky in 1981, the Center for Epidemiologic Studies Depression Scale (CES-D) was used to screen the sample for the presence of depressive symptoms. Using a cutpoint of 29 (rather than the usual cutpoint of 16), 13.7% of men and 18.2% of women were identified as having symptoms of depression. Factors associated with symptoms of depression included older age, education of ≤4 years, income <$4000 per year, housing with ≤two rooms, being widowed, separated, or divorced, and poor health. The strongest association with depression in this sample was physical health. This finding was consistent with data from two prior studies.

These associations were confirmed by an analysis of the ECA sample of community residents aged 60 and older from Piedmont, North Carolina; 19% were diagnosed as having mild dysphoria, 4% had symptomatic depression, 2% had dysthymia, and 1.2% had a mixed depressive anxiety syndrome. Only 0.8% of this sample of older community residents had a diagnosis of major depression. The elderly with symptomatic depression reported poor physical health (3%), the loss of a loved one (25%), reported social phobias, and having experienced social isolation. Community residents with major depression and dysthymia were more likely to report poor physical health, subjective memory problems, subjective negative events, and difficulty with their support networks. The association of illness, disability, isolation, bereavement, and poverty with depression was confirmed by a study of Medicare recipients who resided in the Bronx, New York. Thus, epidemiologic studies of community resident elders in several US cities found a prevalence rate of major depression ranging from 0.8% to 1.8% and a rate for dysthymic disorder of 2%.

The rates of depressive symptoms among medically ill patients has been found to be higher. Stewart et al found 12% of severely medically ill inpatients had depressive illness. In 1967, Schwab et al studied a sample of hospitalized, medically ill patients. Using a clinic interview, depression screening instruments, and the medical record in order to determine the diagnosis, 22% of this sample was found to be depressed. Using the Zung Self-Rating Depression Scale, 42% of the sample of randomly selected outpatients was identified as depressed by clinical examination with only 30% screening positive for depression. Rates of depression among veterans ranged from 13% to 38%.

These data demonstrate that the rate of major depressive disorder is higher among medically ill patients, ranging from 12% to 42%, compared with the rates for various samples of community resident elderly (Table 1). The rate of major depression among medical patients is usually reported as 26%. The association between poor physical health, poverty, impaired support network, bereavement, ≤4 years of education, and an increased report of depressive symptoms and depressive disorders is important in the assessment of the older patient.

Question: What’s the latest on quetiapine and slit lamp examinations?

Dr. Petty: As many of you will know, quetiapine was associated with the development of cataracts in dogs during the clinical studies and there have also been case reports of humans getting cataracts. My own view is that probably it’s no higher than you would anticipate in a population that chronically abuses alcohol and cigarettes, both of which are known to predispose the development of cataracts. The legal situation at the moment has actually been slightly softened in that you can also do direct ophthalmoscopy so long as you are familiar with how to do it in order to pick up early cataracts. In general, the company is still recommending slit lamp examinations on patients on quetiapine at initiation of treatment and every six months thereafter.

Question: Why isn’t AIDS or HIV infection addressed on the risks of depression?

Dr. Gorman: Actually, for a very good reason, and we did a lot of research about this. As far as we can tell, and there’re many studies of this now. Believe it or not, the actual risk or incidence of major depression in people who are HIV-positive is not greater than people who are HIV-negative when the studies are properly controlled. There really is no evidence that there’s an increase in major depressive disorder as a diagnosis in HIV-positive people compared to HIV-negative people. On the other hand, now with the protease inhibitors available, there are some implications for which antidepressant medications to select when you do want to treat an HIV-positive or AIDS patient with antidepressants. I won’t go through all the drug-drug interactions, but its very important when you’re going to initiate antidepressant treatment for somebody on a protease inhibitor to be sure you know exactly which one they’re on and which antidepressant you’re going to pick, because there are some potentially important interactions there.

Question: What do you think about using Parlodel (bromocriptine) for bringing down prolactin levels?

Dr. Petty: Not much. It is something that you can do. There are two drugs that you can use in this indication, one is amantadine, the other is bromocriptine. The difficulty particularly with bromocriptine is that you can exasperate psychosis with it. It’s not common, but it can occur. I also always feel a bit uneasy about using one drug to chase another one if I can possibly avoid it. So I prefer to use one of the prolactin-sparing agents if at all possible. But it can be done. Certainly, I have done it on occasion when it’s been necessary to, as in the old days when we didn’t have the new prolactin-sparing agents. But it’s not what I would recommend. Most of us try to be therapeutic minimalists and use as little as medication as possible with our patients. I would attempt to use prolactin-sparing agents in preference, but you can use bromocriptine and amantadine to bring down prolactin levels.

Question: Does a decrease in REM sleep occur with antidepressant treatment? Is it a problem and if so, how is it treated?

Dr. Gorman: That is a very interesting, complicated issue. You may know there was a study comparing nefazodone to fluoxetine in terms of their effects on sleep. And that was interpreted by the people who wrote it to mean that nefazodone improves sleep quality, but fluoxetine decreases sleep quality. If you actually look at the data, there were very subtle changes on EEG-measured sleep. If you actually asked the patients did they notice any differences, they didn’t. And all of the patients in both groups said that their sleep got better. So there’s a general finding that regardless of what the effect actually is on polysomnographic measures of sleep, they really don’t make that much difference in terms of response or overall outcome. Second of all, there’s another factor when you give SSRIs because the neurons in the median raphe area of the brain that are responsible for manufacturing serotonin are also part of the dream-inducing mechanism of the brain. For example, in cats, if you stimulate that part of the brain, the cat goes into REM sleep automatically. Some people call it the dream machine. So what you’ll often see, paradoxically, is that patients on SSRIs will say after a few weeks that they’re having very vivid dreams and more dreams. And if you’re doing a psychoanalytic treatment with the patient on SSRIs, it’s really great because you get some of the most wonderful dreams. I think that’s why Peter Kramer likes Prozac so much because he’s really a psychoanalyst and enjoys listening to all those increases in dreams. So, in general, we treat insomnia in patients but we don’t treat changes in REM sleep, because they don’t seem to have any real clinical significance as far as we now know.

Question: Should you start withdrawing the conventional drug as soon as you start the new one?

Dr. Petty: I honestly think the best thing to do is to have people on both drugs simultaneously, then gradually reduce the older drug over a period of time. I mentioned as I was talking earlier on, three to four weeks for the older convention agents, probably six to eight weeks for risperidone, and four months for clozapine. The reason being that there is this discontinuation syndrome, which I talked about earlier on, which is very real. It’s not as well described as the SSRI discontinuation syndrome, but it is for real. The very concrete question of how fast do you then reduce the older one? I just take it down in straight increments. So if somebody’s on 40 milligrams of haloperidol, I will reduce it by 10 milligrams a week. This seems to be a safe way to do it and this is what most of the experts in psychosis and most of the pharmacologists are now recommending. As I said earlier on, the silly thing is to simply stop the other drug because you will run into trouble and so will your patient very rapidly, and it’s very foolish to do that. So if you just gradually just have people on two drugs at once.

Question: What do you think about polypharmacy and using two drugs at once?

Dr. Petty: I think that we sometimes have gone a bit too far in trying to be purists and say, only one medicine. I’d like to just think about something for a moment. If you saw a patient in the 1950s with tuberculosis and you said, “What treatment are you on?” and they just said, “It’s Ambutol, you’d say, “And what else?” These days if you had somebody with AIDs, and you said, “What treatment are you on?” and they said “AZT.” You’d say, “And what else?” Because we learned this lesson many years ago, that you often need more than one medicine. Except in psychiatry we’re trying to be purists. We’re all thinking all the time, “Only use one drug.” I prefer to use only one drug, but there are situations where you need to use more than one. And certainly in another question that I’ll come to later on. In the acute situation with psychosis, I see nothing wrong at all with using an atypical and for the first few days using one of the older medications that have more sedative potential. That’s absolutely right and proper. There are many combinations that we have used. You just have to be very smart about understanding drug-drug interactions. And I think certainly my view is that possibly we need to do the same in depression. I wonder what you think, Dr. Gorman?

Dr. Gorman: First of all, I think we should abolish the term, polypharmacy. If the cardiologists and nephrologists can use two drugs then certainly we have to. Because the heart and the kidney are very primitive organs compared to the brain. And the idea that we could really make an impact on an organ that has 100 billion synapses or something like that with one agent is really naпve. There’s data now in bipolar illness that it’s actually quite rare that anyone treats a bipolar patient with only one drug. Most bipolar patients, at least at some points in their lives, are also taking antipsychotic drugs or antidepressant besides taking lithium or valproate. And that’s usually absolutely appropriate and the right thing to do.

Question: Please advise on SSRI increases in prolactin levels.

Dr. Gorman: I actually think there’s not enough research in that area. If you give a serotonin receptor-stimulating drug like fenfloramine, which we can’t use anymore, you do see from an interesting pharmacological mechanism an increase in prolactin level, acutely. So stimulating the postsynaptic serotonin receptor results in an immediate increase in prolactin. However, in SSRI treatment, many of those same receptors actually get down-regulated over time. In general, symptoms secondary to actual prolactin increase are not a major problem and certainly not anyway near the order of magnitude that they are with antipsychotic drugs like the typical drugs and to some extent risperidone. Nevertheless, there are patients who get breast tenderness, galactorrhea from some of the SSRIs. And it’s not even clear if they’re all the same in that regard, some may be different from others. I think that one thing that would actually be important is to study that prospectively more than it’s ever been done.

Question: Halodol seems to be superior to Zyprexa for treating agitation. Please comment on treatment of agitation with atypicals.

Dr. Petty: Yes, I think one of the difficulties that we’ve had with the currently available atypicals is that none of them is sufficiently sedative if you’ve got a very agitated patient in the acute phase. On my own unit at Penn, what we have been doing routinely is that we have clinical pathways. I have now been using olanzapine as my first-line agent. The residents actually call it Vitamin O. But when a patient is agitated, we also give them chlorpromazine for the first few days. I prefer chlorpromazine for a number of reasons, I’ve been using it for more than 20 years. But again, as Dr. Gorman was saying just now. I see absolutely nothing wrong in that situation. We use it for five days. I prefer not using benzodiazepines in acutely psychotic patients because of the relatively high risk of paradoxical effects with them. So this is what we tend to do, actually go and use chlorpromazine together with olanzapine, but we’re always very ready to take it off again after a few days. And that seems to work very effectively and certainly we’ve been doing that for the last 2 Ѕ years. It’s worked with us just fine. I should just mention that there are injectible versions of the atypicals, certainly of olanzapine and ziprazodone in clinical development at the moment and they look like they may actually be pretty effective. The second part of this question actually relates to that and says, “Loxitane seems to have less EPS. Is it an atypical?” Well, some of you who wrote the APA would know that there was a symposium, chaired by Bill Glasser, asking that very question. I would have to say that from my read on the data, it really is not. But again, I don’t really like the term ‘atypical’ because as the new debate is that maybe loxitane the old studies were using too high a dose and if you used a low dose then you don’t get EPS, but you also don’t get much clinical effect. So I really do not think that it’s an atypical.

Question: Dr. Gorman repeatedly uses the term ‘clinician.’ What does that term include?

Dr. Gorman: I usually use the word ‘clinician’ in this context to distinguish between people who actually see patients in real-life settings and people who are seeing patients only in the setting of research clinical trials. There really are legitimate concerns these days not just in psychiatry, but in many branches of medicine. It’s not that we don’t need clinical trials, but they only measure what we call efficacy. They can only tell us in a relatively short period of time if a highly select group of patients who meet all the inclusion/exclusion criteria have a better response to an experimental drug than they do to a placebo or reference drug. And that’s all those trials can tell us. There’s another whole world out there that we call effectiveness which is now that we know this drug is better than placebo in the rare patient with panic disorder who isn’t also depressed and doesn’t drink, etc., etc. Are these drugs any good? Do they really work? Do people actually take them? Can they take them for any length of time? Are they too expensive? Do they require more or less monitoring? I think people have seen the interesting situation with Seroquel, which seems to be a pretty good antipsychotic drug, but the fact that you need to get an eye examination, it does not change its placebo-controlled response in clinical trials, but makes a tremendous difference in terms of whether clinicians can actually use that drug. Because it’s not always easy to accomplish to get that examination accomplished with patients who are in mental health centers and things like that. So that’s the distinction we’re making. We’re really saying that drugs need to be evaluated in real-life clinical settings, not just in the research settings.

Question: Considering the antidepressant effects of novel antipsychotics is a risk of medication induced switch to manic phrase in patients with schizoaffective disorder or bipolar?

Dr. Petty: This has been something that has been of great concern to many of us for some time now. And certainly thought originally that I had patients I had made more manic when I started using olanzapine. Because initially when it came on the market and we had it, I was using it extensively on all sorts of patients to get more hands-on experience, as one should do, I think, with a new medicine, and certainly if you’re in an academic center. I have been less convinced about that as time has gone by, and certainly, I was instrumental at asking Lilly to re-look at some of their own data. Because initially when they were looking at the mood changes when they were initiating treatment, they were actually looking at them after quite long periods of time. They’ve now looked and are doing monitoring of studies every four to six hours over the first few days. And it certainly is the case that some patients do get a little bit of agitation, but not full-blown mania. I think what I was talking about before and I was probably incorrect and I was looking at agitation rather than mania. This incidentally has also been described with risperidone and clozapine. So all of these drugs can cause agitation. I know I mentioned earlier on the anxiolytic activity of risperidone, but it certainly can happen. I don’t believe it’s the case we need to worry about a lot, just be aware that it can happen.

Question: This is a two-part question that asks about the treatment of major depression with psychotic features, and also asks which group of antidepressants has lower potential for secondary mania.

Dr. Gorman: We still firmly believe that the treatment of psychotic depression should be combination therapy of an antidepressant and an antipsychotic drug. I accepted two papers in the American Journal of Psychiatry from Italy which both seemed to show that SSRIs alone were effective in the treatment of psychotic depression. A very difficult decision to accept those papers because the studies were well done. None of the reviewers believed them. But they all seemed to be very well done. We were nervous about not publishing them because we don’t want to suppress information that might lead to further studies. We were nervous about publishing them because we don’t want clinicians to think that’s it’s been absolutely proven and to withhold antipsychotic medication because after all, psychotic depression is probably the most lethal form of depression that we have and the most likely to result in suicide. And also these studies cannot be placebo-controlled because no one is going to take the risk of putting anybody on a placebo with psychotic depression anymore. I’m not entirely convinced by those studies either and there’s a lot of debate about whether the diagnoses were correct, so for now we think that it’s got to be two medications. Now the next part is “Are SSRIs as good as tricyclic antidepressants and even are atypical antipsychotics as good as typical antipsychotics for that particular disorder because to my knowledge, the only real studies of any consequence that have been done in the study of delusional or psychotic depression involve the combination mostly of Trilafon and amitriptyline, and they’re older studies. There are not any really good studies of the SSRI plus an atypical. Most people use that combination and it seems to work, but we don’t have any systematic data. Most patients with psychotic depression are going to get hospitalized and we recommend now combining an atypical antipsychotic with an SSRI in those patients, but you should know that the data for that are not entirely secure. In terms of which group of antidepressants are less likely to induce mania, again, that is not a properly studied area at all. There is an idea in the field that bupropion is less likely to produce mania than other antidepressant drugs. That’s probably not true. The study that we’ve seen recently, I don’t know if it’s published yet, actually compared I think it was paroxetine to bupropion for the treatment of bipolar patients in the depressed phase. And it actually did show that buproprion was less likely to induce mania than paroxetine, but that was because buproprion was less likely to make the depression any better. So obviously buproprion was not a very good choice in that situation. Tricyclics and MAO inhibitors clearly have the potential to induce mania. SSRIs clearly induce mania. I would say you should pick the drug that you think is best for the patient and watch for mania and treat that and not rely on any class being any better than any other class at the present time.

Question: How long should a patient with paranoid schizophrenia keep taking antipsychotics? For life or what?

Dr. Petty: If you have a first-episode illness, treatment should be continued and these are the APA guidelines, for one year. If they have had two or more, it is five years. If they’ve have had more than that, it is recommended it is going to be lifetime therapy. Nobody wants to commit somebody to a lifetime treatment and that’s why it is so important to get the diagnosis right at the beginning, and why we need to be so careful.

Question: Does the risk of Parkinson’s justify continued treatment?

Dr. Petty: The take-home message is that the risk of Parkinson’s is so much lower with quietiapine and olanzapine. It’s also lower with low doses of risperidone, but again if you hit 5 or 6 milligrams, it begins to rise quite rapidly. So it’s not so much of an issue as it was. So one episode–one year; two or more-five years; more than that-lifetime.

Question: What antidepressant is best for the depressed patient with AIDS or HIV-infection?

Dr. Gorman: There are few studies of this. One controlled study showed tricyclics worked very well and were surprisingly well-tolerated. Judy Rabkin’s group at Columbia had a nice controlled trial of fluoxetine and showed that it was very well-tolerated and very effective. And a group at the University of Houston, led by Francisco Fernandez, has shown over and over again that psychostimulants are very useful, although I don’t think those have been controlled trials. So a variety of antidepressants work. In terms of what’s the best, really it’s again, like any other depressed patient, you’re picking based on the actual presentation of the depression, and in this case, very carefully looking at potential drug-drug interactions, because there are important drug interactions between protease inhibitors and some antidepressants. But for example, if a patient with HIV infection is not sleeping, one would want to pick an antidepressant that might help them sleep. If their appetite’s not very good, one would perhaps want to pick one that increases appetite. We’re usually picking from among managing various side effects, but as far as we know, the only really good studies have shown that fluoxetine and desipramine are effective.

Question: Can you comment on atypicals, e.g., risperidone to augment severe refractory OCD?

Dr. Petty: There are some clinical trials looking at some atypicals on their own. Many experts have actually also been trying to use atypicals, all of them, in fact in the treatment of OCD. Olanzapine may be a shade better than risperidone, but as I say, this is anecdote, it has not been formally examined. It is certainly possible to use them in severe OCD. I have done it several times. I have one particularly difficult patient who’s actually been in inpatient care for six years, whose life has changed dramatically when we took him off the 80 milligrams a day of haloperidol he was on, in addition to fluvoxamine and all the rest. He’s now on eight milligrams, instead of 80, together with 20 of olanzapine and the symptoms are considerably better on that regimen.

Question: What happens if SSRIs don’t work?

Dr. Gorman: It is reasonable to try clomipramine if two SSRIs have not been effective, Sometimes a patient will respond to that who didn’t respond to an SSRI. In terms of augmentation, almost every augmentation attempt when studied has been a failure. Lithium has been shown not to be effective. Buspirone has not held up in controlled trials as an effective augmenter in OCD patients or SSRIs or clomipramine. And as Dr. Petty mentioned, the only thing that actually has been shown to work is the addition of antipsychotic medication. But really only in two situations. Antipsychotic medications enhance antidepressants in OCD patients who also have tics, or in OCD patients where the obsessional content is almost delusional. In those two cases, they work. In the tic situation, both pimazide and haloperidol have shown to be enhancing. In the delusional area, I think the atypicals have proven to be the best. Those are what have been shown, in addition to that, we have an interesting paradox which is that patients with schizophrenia treated with atypical antipsychotic agents, we sometimes see the new onset of OCD symptoms and that’s believed to be secondary to the blockade of the 5HT2 receptor. However, in OCD patients who have not had a complete response to clomipramine or an SSRI, we often see improvement when we add risperidone or olanzapine. No one knows exactly why that is, but the first thing we usually try now in a refractory OCD patient, after trying at least two SSRIs and clomipramine, is to add olanzapine or risperidone to their regimen and that seems to work for a surprisingly large number of patients.

Question: How often do you monitor your patients and how often do you see them?

Dr. Petty: As often as is necessary. We try and spend as much time a night, make a lot of use of other people who are treating them-ICMs and family, in particular, to try and see them. In the initial stages, try to see patients once a week. I am also quite allergic to infantilizing patients with psychotic illnesses. I think it is a serious mistake to treat them like children, because they usually respond by behaving like children. So I try to give them some autonomy. But also make quite sure they know where to come and what to do if they run into any kind of trouble.

Psychiatric Problems in Children

Tranquillizers have been used to a moderate degree in the treatment of similar psychiatric conditions in children, as in the anxiety reactions and the associated somatic symptoms. They are also of value in childhood schizophrenia. Promethazine has been a particularly helpful drug with very minimal side effects. Promazine and thioridazine have proved to have a similar function. Children who have such problems as speech defects, enuresis, sleepwalking, and nightmares may be helped by several months of therapy with these medications. Deanol has been recommended for behaviour disorders, as have drugs of the amphetamine group, such as dextroamphetamine. Caution should be exercised in the use of the more recently developed phenothiazines of higher potency, as a syndrome suggesting brain tumour, encephalitis, meningitis, and tetanus has been noted in children in association with their administration.

In conclusion, it may be stated that the advent of the tranquillizer drugs represents a considerable advance in the treatment of psychiatric patients, particularly those with a psychosis. Antidepressant drugs have improved the management of depressions and decreased the need for electroshock treatment, although this treatment is still indicated for patients who have severe depressions with suicidal drives. These drugs have decreased significantly the length of hospital stay, permitting improved rehabilitation of the patient within his community.

Miscellaneous Group

The drugs in the miscellaneous group which are most widely used are meprobamate and Librium.

Meprobamate is marketed under the trade names of Equanil, Miltown and Tranquiline. It has presented minimal toxic effects but has been misused by many people prone to drug addiction. The drug is essentially an effective medication for anxiety reactions but should be avoided, or at least used with considerable caution, in individuals with character disorders, alcoholism or previous drug addiction.

A new tranquillizer, unrelated chemically to any of the other drugs, is Librium. It would seem that this drug will be of value in anxiety states, neurotic depressions and obsessive-compulsive neuroses. The side effects are minimal, mainly in the form of drowsiness and ataxia which can be handled by lowering the dosage. These side effects are more likely to occur in elderly and debilitated patients and require caution in initial medication levels. The effect of Librium is the reduction of anxiety and tension; and in some cases stimulation may occur. Many patients have reported improved appetite and weight gain on this drug.

Antidepressants

There are many drugs available for use in the treatment of neurotic depression and fatigue states. Traditionally, the amphetamines such as Dexedrine and Benzedrine have been effective for this type of depression, mainly by producing euphoria and increased psychomotor activity. They are of little value in the more serious depressive illnesses, Side effects of tremor, palpitations and poor appetite occur. Methylphenidylacetate (Ritalin) is a most useful drug for the mild to moderate depressions and can be administered safely to the elderly patient and to patients with serious medical disabilities such as coronary artery disease. The side effects are minimal. Deanol (Deanor) is another drug without appreciable toxic effects which is of value in the neurotic depressions. Librium also shows considerable promise in its effect on depression.

For the psychotic depression, two groups of drugs are used: the amine oxidase inhibitors and imipramine (Tofranil). Iproniazid (Marsilid) was the first of the amine oxidase inhibitors to be introduced. This is an inhibitor of the enzyme monoamine oxidase. The resultant effect is an increase in brain serotonin which may affect neurohormonal control at the synapse. Iproniazid was found to be effective in psychotic depressions that had not responded to electroshock treatment and was considered to facilitate recovery in these depressions in conjunction with other methods of treatment. Serious toxic effects were reported, mainly in the form of liver cell damage and, in some cases, acute hepatic necrosis. It is felt, however, that these toxic effects were due to excessive dosage. The drug has subsequently been considered reasonably safe in lower dosage levels with close clinical supervision. Similar drugs of less, toxicitv have been marketed, namely, phenylzine di-hydrogen sulfate (Nardil) and nialamide (Niamid). Their indication and method of action are similar to those of iproniazid. Side effects of vertigo, dry mouth, perspiration, ankle edema and hypotension have been reported. Dosage levels in this group should be reduced to maintenance levels after two to three weeks with adequate medical supervision. In summary, the indications for the amine oxidase inhibitors are as follows:

(1) For the treatment of low-grade depression not requiring hospitalization and without suicidal risk.
(2) For the management of serious depression in hospital, usually in conjunction with electro-convulsive therapy.

Imipramine (Tofranil) is the other drug to be considered in this antidepressant group. It is closely related chemically to the phenothiazine group but has no action as a tranquillizer and is not an amine oxidase inhibitor. It does, however, increase the level of brain serotonin and has some action on the central nervous system function at the synapse. Its side effects include dryness of mouth, blurring of vision, hypotension, tachycardia, and with high dosage, urinary retention. In view of the hypotensive effect, it should be used with caution in elderly persons and patients with cardiac failure or coronary heart disease. Dosage levels of 25 mg. four times daily are adequate and it is doubtful if higher levels are of value. After recovery from the depression, maintenance treatment with 25 mg. daily should be carried on for one or more months.

Experience indicates that the more serious depressions will not respond to drug management within a short time and that hospitalization is advisable to protect the patient from suicide and to provide adequate care. Electroshock treatment is indicated in conjunction with drugs in this group for the severe depressions with suicidal drives and for the group of patients who do not respond satisfactorily after an adequate trial with medication alone.

A healthy controversy continues to be manifested in the field of psychiatry concerning the use of drug therapy. This controversy is related to the following factors:
(a) The complexity of new drugs and the multiplicity of drugs offered from month to month to the physician.
(b) The difficulty in determining the effect of the drug as distinct from the psychological influence of placebo administration.
(c) The pressure on the physician for medication trials due to the distress of the patient and his need for a dramatic therapeutic procedure.

The drugs which will be considered in this paper are the tranquillizers and the antidepressants. A tranquillizer may be thought of as a drug effecting reduction of anxiety with minimal disturbance of concentration and memory. The drug acts primarily on the reticular structure of the brain stem and midbrain area, as compared with the sedative that has mainly a cortical site of action. The advantage of the tranquillizer is that it relieves anxiety and tension without disturbing high-level thought processes. Consequently it is useful for the ambulant patient who remains at work, and is of value in his psychotherapeutic treatment.

The antidepressants are specific drugs designed to counteract depression and have little effect on anxiety. They constitute a considerable advance in psychiatry, have reduced the use of electroshock treatment, and have facilitated the treatment of some depressive states on an office-patient basis. They have also prevented the recurrence of depression after successful treatment in hospital.

Principles Involved in Drug Management

It is necessary to have an adequate knowledge of the patient’s psychiatric background and physical health before determining the use of medication. It is to be remembered that a drug does not substitute for the doctor-patient relationship. Familiarity with the action, side effects and toxicity of any new drug in this field should be firmly established before it is prescribed, and the physician should change only with caution to a new drug offered in this area. The cost of drugs remains an important factor in their choice, as therapy may involve several months of medication. The author’s impression of the usefulness of these drugs is based on experience in the field of private practice in psychiatry and will differ somewhat from the indications applicable in a mental hospital setting.

The tranquillizers are mainly differentiated in three groups:
(1) the rauwolfia alkaloids,
(2) the phenothiazine derivatives, and
(3) a miscellaneous group such as meprobamate and hydroxyzine hydrochloride.

Rauwolfia Alkaloids

The rauwolfia alkaloids have been advocated for their tranquillizing effects and were the subject of research studies initiated in 1947. The alkaloid utilized for this purpose is reserpine. In 1950 clinical trials showed that this drug possessed a tranquillizing effect. It was also found to produce lowering of blood pressure and slowing of heart rate. It was consequently used in a wide range of psychiatric conditions, but in some cases precipitated acute depression and reactivation of psychotic symptoms. The unpredictability of its effects has made it a difficult drug to use in psychiatric practice outside the mental hospital.

Phenothiazine Derivatives

The phenothiazine derivatives include a considerable number of drugs, some of which are promethazine (Phenergan), chlorpromazine (Largactil), promazine (Sparine), thioridazine hydrochloride (Mellaril), trifluoperazine (Stelazine), perphenazine (Trilafon), and levomepromazine (Nozinan).

Promethazine was initially used as an antihistaminic and was found to have tranquillizing effects. This led to the study of related compounds, principally chlorpromazine. This drug rapidly found a wide range of usefulness in the medical fields of anesthesia, surgery, obstetrics, gynecology and psychiatry. Chlorpromazine was first synthesized in France in 1950 and introduced clinically in this country in 1954. In addition to its effects as a tranquillizer, it has an antiemetic action, as well as a potentiating influence on the effects of barbiturates and alcohol. Cardiovascular changes, particularly hypotension and tachycardia, were observed in association with this drug. It was soon recognized that chlorpromazine produced marked reduction of anxiety and was especially useful in states of excitement as found in the manic psychoses and acute delirium. In addition, chlorpromazine was found to be of value in schizophrenia, rendering the patient better able to manage the stresses of everyday living. It improved the treatment situation in mental hospitals, rendering patients more accessible to psychotherapy and other methods of treatment. The indications for the other phenothiazine derivatives are much the same as those outlined for the use of chlorpromazine. There is, however, a considerable difference in dosage range for patients in the ambulant group. The following doses are recommended for the various drugs in this group:

Chlorpromazine 25-50 mg. four times daily
Promazine 50-100 mg. four times daily
Thioridazine 10-25 mg. thrice daily
Trifluoperazine 2-4 mg. thrice daily

Perphenazine 4-8 mg. thrice daily Their side effects include tachycardia, accommodation disturbances, hypotension and drowsiness. The more serious side effects, such as parkinsonism, occur at high dosage levels, particularly in association with the drugs trifluoperazine and perphenazine. These, however, can be controlled by reduction of dosage or by the use of Cogentin. The serious toxic effects, agranulocytosis, jaundice and skin rashes, are related to sensitivity of the patient to the drug. The jaundice apparently occurs on the basis of obstruction of the bile canaliculi, with no effect on the liver parenchyma. The condition is reversible, usually in two or three weeks after cessation of drug therapy. It does not preclude the use of chlorpromazine, although this complication may be a source of worry to some physicians. The total experience is that this group of drugs is essentially safe under clinical supervision.

Clearly, depression is a known and expected consequence of cocaine withdrawal directly related to the mechanism of action at the presynaptic nerve terminals. However, as previously noted, certain people with severe pre-existing depression may unconsciously use (abuse) cocaine to treat this condition. We have recently encountered two such people.

The first was a 39-year-old man who participated in one of our research studies. He used cocaine intravenously in relation to situational (i.e., reactive) depression. He reported that he had started cocaine use about 6 months earlier because of depression related to a recent divorce and was using up to 8 g (i.e., 30 to 40 injections) daily. He said “I never did street drugs in my life until 6 months ago. … I would never have started if I wasn’t lonely.”

The second was a 30-year-old man who had first started using cocaine at 20 years of age and was injecting himself with about half a gram of cocaine once a month when first seen. Clinical interview and psychometric assessment revealed a history of chronic (apparently endogenous) depression that he had treated periodically with cocaine. Cocaine abuse in this patient was successfully treated with a combination of fluoxetine (Prozac) and intensive psychotherapy. He has now been drug free for over 6 months. (In addition to its use in the treatment of depression fluoxetine (Prozac) may have some direct pharmacologic effect in reducing the self-administration of cocaine.)

Obviously, not all cocaine-dependent patients will have a dual diagnosis. However, for those with comorbid depression, clinicians should consider the possibility that the depression may be a cause rather than a result of cocaine abuse. Hence, treatment of the cocaine abuse without appropriate treatment of the underlying depression may well result in relapse and related sequelae.