Janimine

Psychostimulants for Depression in the Medically Ill The treatment of depression in medically ill patients presents many challenges. Often, the use of tricyclic antidepressant drugs is precluded by the patient's physical condition. In addition, the two- to three-week delay between initiation of tricyclic therapy and clinical improvement in dysphoria may be troublesome. [1,2] The consequences of depression, such as loss of appetite, pessimistic thinking, impaired immunity, delayed wound healing, and inability or unwillingness to participate in self-care, can have negative ramifications for very ill persons. [3] Thus, an alternative pharmacologic treatment with rapid onset of action and minimal side effects is needed for medically ill patients who are depressed.

The use of psychostimulants, such as dextroamphetamine (Dexedrine) or methylphenidate (Ritalin), is an option that should be considered [4] (Table 1). The common biologic action of amphetamine and methylphenidate is potentiation of dopamine and norepinephrine within the synaptic cleft. [5] Increased concentrations of these neurochemicals have been associated with alleviation of depression. Indeed, most antidepressant drugs exert their therapeutic effects by a similar mechanism.

Dextroamphetamine

and Methylphenidate

Dextroamphetamine, which is the Disomer of amphetamine, and methylphenidate are indirect-acting sympathomimetic agents (Table 2). Their primary action on the central nervous system is to potentiate the effects of norepinephrine and dopamine at the synapse. [5,6] Relief from depression with a brief trial of dextroamphetamine or methylphenidate is reported to be a predictor of a positive antidepressant effect from imipramine (Janimine, Tofranil) or desipramine (Norpramin, Pertofrane). [7-9] Lack of response to a psychostimulant is thought to predict possible therapeutic success with amitriptyline (Elavil, Endep) or nortriptyline (Aventyl, Pamelor). [7]

Because of fears about drug abuse and a widely held view that psychostimulants are of limited usefulness in patients with depression, the use of dextroamphetamine is largely restricted to the treatment of narcolepsy and methylphenidate is chiefly prescribed for attention deficit disorder and hyperactivity. Recent reports in the literature suggest that these drugs should be considered in some cases of depression. [10-14] A double-blind study of 18 depressed patients demonstrated the superiority of amphetamine over placebo in improving mood and psychomotor activation. [15] Another study [2] described the efficacy of dextroamphetamine in potentiating analgesia and relieving despondency in depressed patients with severe pain.

Proper patient selection is important when psychostimulants are being considered for treatment of depression. Medically ill persons who exhibit neurovegetative signs such as psychomotor retardation, apathy, low motivation and hypersomnia are considered good candidates. [14] In a study of 66 medical and surgical patients who received dextroamphetamine or methylphenidate to treat a depressive disorder, 75 percent showed improvement. [1] For 50 percent of these patients, progress was marked to moderate, with 93 percent reaching peak response within two days. Side effects were minimal, consisting primarily of confusion in elderly patients with previous cognitive impairment. The confusion remitted with discontinuance of the drug.

Another report [16] has described the beneficial effects of psychostimulants in treating depression in patients infected with human immunodeficiency virus (HIV).

Assessment of clinical response to psychostimulants may be secondarily helpful in the differentation of depressive pseudodementia from true cognitive impairment. [17] When given a trial of a psychostimulant, patients with pseudodementia often show significant improvement in their cognitive state, while patients with true dementia generally respond to such medication with heightened cognitive impairment. [17]

Studies also suggest that methylphenidate has a potentiating effect on blood levels of tricyclic antidepressants. [1,2,6,10]

Obviously, correctable causes of mood disorders, such as thyroid disease, anemia, cerebrovascular accident and adverse effects of medications (especially antihypertensives and corticosteroids), should be searched for and appropriately treated before a patient's dysphoria is attributed to a psychiatric condition.

Prescribing Psychostimulants

for Depression

The average dextroamphetamine dosage used in our patients is 10 mg a day, with a range of 2.5 to 30 mg. Some studies [1,2] suggest that the dosage may be increased to 60 mg per day, but we have not found it necessary to exceed 30 mg. A typical starting dose is 5 to 10 mg, given in the morning because of the drug's activating effects and its long half-life (up to 21 hours). [1,2] The dose can then be increased by 5 mg every 24 hours until the desired dosage or clinical effect is achieved. Most patients show some response after 48 hours; many respond after the initial dose.

Because the half-life of methylphenidate is two to seven hours, this agent is usually given at 7 and 11 a.m. or at 8 a.m. and noon. We generally start with a total dosage of 5 to 10 mg per day, given in doses of 2.5 to 5 mg twice daily. On the second day, the dosage is doubled; it is then increased until the desired effect is obtained. In our patients, 40 to 50 mg has been the maximum daily dosage; however, some studies advocate dosages approaching 90 mg per day if necessary. [1,2]

Although the use of psychostimulants for periods up to one year has been reported, most of our patients receive these agents for one to three weeks. Improvement has been noted in all neurovegetative signs of depression, including insomia and anorexia. Few instances of psychostimulant abuse have been seen among our patients or others reported in the literature. [1,2,10,11] The major side effects in our patients have been tachyarrhythmias (presumed to be secondary to the use of psychostimulants) and an increase in anxiety among patients with agitated depression.

Some physicians substitute a more traditional antidepressant medication after two to three weeks of psychostimulant treatment when the patient's physical condition has improved. The more activating drugs (e.g., desipramine, protriptyline [Vivactil]) are generally used in this instance. A "wash-out" period of two weeks is recommended before beginning monoamine oxidase (MAO) inhibitors (e.g., phenelzine [Nardil]) after amphetamine or methylphenidate use.

Relapse while the patient is taking the stimulant and recurrence of symptoms once the drug has been discontinued appear to be much more common with methylphenidate than with dextroamphetamine. If relapse occurs during methylphenidate therapy, a change to dextroamphetamine may alleviate the symptoms. Some studies suggest that dextroamphetamine is more beneficial for patients with major depression while methylphenidate is superior in those who have adjustment disorder with depressed mood. [1,2,16]

The following cases illustrate the use of psychostimulant therapy in patients with a variety of medical illnesses.

Illustrative Cases

CASE 1

A 40-year-old man was evaluated in a psychiatric clinic because of depression and suicidal ideation. He had been diagnosed as having acquired immunodeficiency syndrome one year previously, and he had deteriorated physically since that time. The patient reported extreme lethargy, poor concentration, anorexia, reclusiveness, anhedonia and recurrent, intrusive thoughts of suicide. He had already devised a plan by which he intended to take his life. A series of antidepressant medications, including doxepin, trazodone and desipramine, had been tried; all had to be discontinued because of poor response or debilitating side effects.

The patient had accepted his poor prognosis, but he desired enough energy and motivation to "make the most of the time I have left." An organic work-up included electroencephalogram, computed tomography (CT) of the head and magnetic resonance imaging (MRI), all of which gave negative results. None of his medications were likely to cause depression, and he denied alcohol or illicit drug use. Zidovudine (Retrovir) had been prescribed, but his hemogram was normal.

The patient was started on methylphenidate, 5 mg before breakfast and lunch. The dosage was increased to 10 mg twice daily on the third day, and to 10 mg three times daily (at 7 a.m., 10 a.m. and 1 p.m.) on the sixth day. Within 24 hours of the initiation of methylphenidate, the patient noted improvement in his sleep, appetite and energy level. After two weeks of treatment, he had gained weight, he was again able to attend support groups, and he no longer contemplated suicide. He denied any side effects from the medication, except for a mild increase in anxiety that remitted after the first few days of therapy. After three months, the dosage was decreased to 10 mg twice a day, without evidence of physiologic withdrawal. The patient continues to do well on this dosage.

This case illustrates the efficacy of psychostimulants in medically ill individuals whose condition precludes the use of more traditional agents. Most patients with AIDS receive a variety of medications, and drug interactions commonly occur between tricyclic antidepressants or MAO inhibitors and drugs for AIDS. The low side-effect profile and the quick onset of action of psychostimulants are of particular benefit in these patients.

CASE 2

A 78-year-old woman was hospitalized because of shortness of breath, hypersomnia

and refusal to eat. She had a history of myocardial infarction, hypertension, glaucoma and depression. After stabilization of the patient's cardiac and pulmonary status, the attending physician requested a psychiatric consultation to evaluate her dysphoria.

An electroencephalogram, CT scan of the head and results of thyroid function studies were unremarkable. Cimetidine and methyldopa were discontinued because of their potential adverse effects on mentation. The patient's mood, however, remained dysphoric. After considering the patient's cardiac history, the psychiatrist suggested inpatient psychiatric care and evaluation for electroschock therapy, which had successfully resolved her previous depression. The patient and her family refused these suggestions. The patient was then started on methylphenidate, 2.5 mg at breakfast and at lunch. Her cardiac status was monitored carefully for new-onset arrhythmias.

Within 36 hours, the patient was able to sit in a chair and consume a liquid diet. Her methylphenidate dosage was gradually increased to 10 mg twice a day, and her mood improved considerably. She received the medication for 90 days; it was discontinued without withdrawal symptoms or relapse.

This case illustrates the use of psychostimulants in medically ill elderly patients. Other potential causes of a mood disorder should be investigated before the physician decides that despondency has a functional, rather than an organic, etiology. The side effect most likely to occur in elderly patients receiving psychostimulants is the new onset of confusion; this did not occur in the patient described. While the new serotonin reuptake inhibitor fluoxetine (Prozac) has some efficacy in such individuals, the delayed onset of antidepressant action with this agent ws unacceptable in this patient.

CASE 3

A 50-year-old man was evaluated by a psychiatric consultant 72 hours after cardiac transplantation. According to the transplant team, this patient had "lost his will to live." Specifically, he refused to eat, slept all day and would not participate in his care. His depression was seriously undermining his recovery from surgery, although metabolic parameters were stable.

The psychiatrist prescribed methylphenidate at a dose of 2.5 mg twice a day. This dosage was maintained for 24 hours with little effect. Over the next three days, the medication was increased to 10 mg twice a day. The patient's energy level increased considerably. He became more communicative and animated, and his appetite improved greatly.

As a result, the patient's medical condition improved, and he was able to leave the intensive care unit. He did have an episode of ventricular tachycardia, which could have been related to the methylphenidate. The arrhythmia responded well to quinidine. Nonetheless, the methylphenidate was tapered and discontinued after three weeks. The patient was discharged.

About three weeks after discharge, the patient was readmitted with symptoms of apathy, low motivation and psychomotor retardation. Again, no medical explanation for these symptoms was found. On this occasion, the psychiatrist selected dextroamphetamine because of its usefulness for patients with major depression and for those who relapse after methylphenidate therapy. The patient responded well to this medication. His cardiac rhythm was stable. This patient is currently receiving dextroamphetamine at a total dosage of 15 mg daily. The plan is to continue the medication for a total of 60 to 90 days.

CASE 4

A 37-year-old man was referred for evaluation of congestive heart failure of three months' duration. Cardiology evaluation revealed global hypokinesis with marked biventricular dilatation. Left ventricular ejection fraction was 16 percent. In addition, the patient's decreased flow state had resulted in compromised hepatic and renal function.

The patient was uncooperative and refused to allow the physicians to proceed with the evaluation, even though his condition was rapidly deterioraing. Without appropriate medical care, he was expected to die in four to six weeks.

Psychiatric consultation revealed that the patient was a recent widower and the father of two small children. On mental status examination, he displayed paucity of speech, sad affect, emotional lability and poor concentration. In addition, he was experiencing sleep and appetite problems. These symptoms had persisted for eight months. The psychiatrist wondered if the patient's failure to cooperate with possibly lifesaving medical intervention was a reflection of his severely depressed state.

The psychiatric differential diagnosis was grief reaction versus major depression. Because of the patient's compromised physical status, the psychiatrist was concerned that a tricyclic antidepressant or MAO inhibitor would only create additional problems. Furthermore, the usual lag time associated with standard antidepressants was unacceptable in view of the patient's rapid deterioration.

Dextroamphetamine therapy was started at 5 mg every morning. Within 24 hours, the patient's affect was markedly improved. He began to interact with staff and to initiate conversations with his family and friends. Most important, he agreed to the evaluation and transplantation, both of which he had earlier refused. He has since undergone a cardiac transplantation and is progressing well.

CASE 5

A 60-year-old woman was hospitalized after complaining of several episodes of lower extremity weakness and near-syncope of uncertain etiology. She had also experienced nausea, vomiting and anorexia. This patient had a history of kidney disease, and a hemodialysis shunt had been placed. The hemogram and routine chemistries performed at admission were normal, but the erythrocyte sedimentation rate was 150. CT scanning of the head and spine showed evidence of a mass at the level of T12, and MRI indicated that the mass was extradural. Vital signs disclosed postural hypotension and tachycardia.

Family members reported that the patient had been quite depressed before the onset of these symptoms. A psychiatric consultation revealed that she had sustained a series of recent losses, including the deaths of her sister, her mother and her husband of 45 years.

On mental status examination, her mood was dysphoric. She was not disoriented, psychotic or otherwise cognitively impaired. She did complain of fatigue, low motivation, hypersomnia and psychomotor retardation. The patient was not suicidal.

The psychiatrist diagnosed major depression and unresolved grief. Because the patient's depression was compromising her medical treatment, antidepressant medication was indicated. The psychiatrist was concerned about the hypotensive effects of tricyclic antidepressants and MAO inhibitors, and about the propensity of the former to exacerbate tachycardia. Fluoxetine was not an option because of its potential gastrointenstinal side effects. The consultant eventually decided on doxepin at a very low dosage, reasoning that the drug's [H.sub.2] receptor antagonist action might improve the patient's gastrointestinal distress as well.

After an initial bedtime dose of 25 mg of doxepin, the patient complained of marked dizziness and near-syncope. Doxepin was discontinued and methylphenidate was begun at 2.5 mg twice daily. The dosage was increased to 5 mg twice daily, and the patient's energy, mood and appetite improved in less than 36 hours. She was much more animated and began to cooperate with the diagnostic examinations. A mylelogram was performed and was negative.

Methylphenidate was continued for five days; the only side effect was a mild tremor. After the patient's renal and cardiovascular condition was stabilized, the psychostimulant was discontiued without evidence of withdrawal symptoms or return of depression. The psychiatrist suggested follow-up counseling at a local mental health facility.

Final Comment

Major depression is a frequent finding in medically ill individuals. In such cases, the disturbance in mood can adversely affect recovery and may even increase mortality. Given the precarious physical condition of these patients and the need for rapid alleviation of depression, traditional antidepressant medication is often not a reasonable option.

In the five illustrative cases, dosage and duration of psychostimulant treatment varied, but all patients improved significantly after 36 hours. Side effects included tremor and possible ventricular ectopy, both of which resolved. Drug habituation did not occur. Potential tricyclic antidepressant side effects, such as postural hypotension, urinary retention, decreased gastrointestinal motility, ventricular conduction delays, seizures, blurred vision, dry mouth and hematopoietic disturbances, were avoided.

The primary difficulty we have found in using psychostimulants for depression is of the other medications that patients on psychostimulant therapy are taking, the methylphenidate or dextroamphetamine is invariably blamed for all medical complications.

It will take some time for physicians to feel comfortable prescribing these agents, which ironically are much safer than tricyclic antidepressants. Primary care physicians should consider psychostimulants in their medically ill depressed patients for whom traditional antidepressant pharmacotherapy is either too risky or too slow. Physicians who decide to prescribe these medications for outpatient treatment of depression should be aware that the patient's diagnosis must appear on the prescription form.

REFERENCES

[1.] Woods SW, Tesar GE, Murray GB, Cassem NH. Psychostimulant treatment of depressive disorders secondary to medical illness. J Clin Psychiatry 1986;47:12-5.

[2.] Kaufmann MW, Murray GB, Cassem NH. Use of psychostimulants in medically ill depressed patients. Psychosomatics 1982;23:817-9.

[3.] Calabrese JR, Kling MA, Gold PW. Alterations in immunocompetence during stress, bereavement, and depression: focus on neuroendocrine regulation. Am J Psychiatry 1987;144:1123-34.

[4.] Satel SL, Nelson JC. Stimulants in the treatment of depression: a critical overview. J Clin Psychiatry 1989;50:241-9.

[5.] Moore KE. The actions of amphetamine on neurotransmitters: a brief review. Biol Psychiatry 1977;12:451-62.

[6.] Tesar GE. The role of stimulants in general medicine. Drug Therapy 1982;12:186-98.

[7.] Sabelli HC, Fawcett J, Javaid JI, Bagri S. The methylphenidate test for differentiation of desipramine-responsive from nortriptyline-responsive depression. Am J Psychiatry 1983;140:212-4.

[8.] Fawcett J, Siomopoulous V. Dextroamphetamine response as a possible predictor of improvement with TCA therapy in depression. Arch Gen Psychiatry 1971;25:244-7.

[9.] van Kammen DP, Murphy DL. Prediction of imipramine antidepressant response by a one-day dextro-amphetamine trial. Am J Psychiatry 1978;135:1179-84.

[10.] Fernandez F, Adams F, Holmes VF, Levy JK, Neidhart M. Methylphenidate for depressive disorders in cancer patients. An alternative to standard antidepressants. Psychosomatics 1987;28:455-61.

[11.] Katon W, Raskind M. Treatment of depression in the medically ill elderly with methylphenidate. Am J Psychiatry 1980;137:963-5.

[12.] Kaufmann MW, Cassem N, Murray G, McDonald D. The use of methylphenidate in depressed patients after cardiac surgery. J Clin Psychiatry 1984;45:82-4.

[13.] Kaplitz SE. Withdrawn, apathetic geriatric patients responsive to methylphenidate. J Am Geriatr Soc 1975;23:271-6.

[14.] Moore DP. Methylphenidate in depression and states of apathy. South Med J 1981;74:347-8.

[15.] Silberman EK, Reus VI, Jimerson DC, Lynott AM, Post RM. Heterogeneity of amphetamine response in depressed patients. Am J Psychiatry 1981;138:1302-7.

[16.] Holmes VF, Fernandez F, Levy JK. Psychostimulant response in AIDS-related complex patients. J Clin Psychiatry 1989;50:5-8.

[17.] Goff DC. The stimulant challenge test in depression. J Clin Psychiatry 1986;47:538-43.

The Authors

ROBERT L. FRIERSON, M.D. is associate professor of psychiatry and behavioral sciences and director of Consultation/Liaison Psychiatry at the University of Louisville School of Medicine, his alma mater. He also completed residencies in family medicine and psychiatry and a fellowship in the Department of Consultation/Liaison Psychiatry at the University of Louisville School of Medicine.

JOHN J. WEY, M.D. is completing a child psychiatry fellowship at the University of Washington School of Medicine, Seattle. A graduate of Wright State University School of Medicine, Dayton, Ohio, Dr. Wey served a residency at the University of Louisville School of Medicine.

JAMES BOSWELL TABLER, M.D. is in private practice in Louisville and is the psychiatric consultant for the Jewish Hospital Institute for Heart and Lung Disease, also in Louisville. Dr. Tabler received his medical degree from the University of Louisville School of Medicine, where he also completed a residency in general psychiatry and a fellowship in the Department of Consultation/Liaison Psychiatry.

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