USE OF STIMULANTS IN THE MEDICALLY ILL

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Amphetamine was first synthesized in 1887 by the German pharmacologist Edeleano,83 though in 1910 it was Barger and Dale5 who studied its effects on sympathomimetic amines. In 1932, the benzedrine inhaler (containing D, L amphetamine) was introduced into the American market.83 The first major review of amphetamines in 1939 cited at least 16 different indications for the drug.98

The hardships of World War II led to amphetamine's use by the German Panzer troops as well as by Japanese, British, and American forces.124 By 1970, production of amphetamines had risen to 10 billion legally and countless more in the black market.124 The “speed freak” epidemic of the 1960s gave amphetamines a black eye; the subsequent crackdown led to governmental restriction of amphetamines for use only for narcolepsy, attention deficit hyperactivity disorder (ADHD), and refractory obesity.124 Recently, renewed interest in their use has been stimulated in other patient populations, most notably depressed medically ill patients and patients with refractory primary depression.36, 53, 108

Depressive disorders are extremely common in medically ill patients including those with heart disease, stroke, Parkinson's disease, diabetes, and epilepsy. The tricyclic antidepressants (TCAs) are associated with anticholinergic side effects (e.g., dry mouth, constipation, urinary retention, tachycardia); cardiac conduction system abnormalities (e.g., increased QTC interval); orthostatic hypotension; sedation; and weight gain. In addition, they are toxic in overdose. In fact, in one study96 TCAs were discontinued in one third of patients with medical illnesses owing to side effects, a much higher rate of discontinuation than is seen among psychiatric inpatients or patients without comorbid medical illness. The selective serotonin reuptake inhibitors (SSRI's) cause nausea, headache, sexual dysfunction, and jitteriness and can also have drug interactions owing to their inhibition of cytochrome P450 isoenzymes.

TCAs and the newer standard antidepressants also have a long latency of response (i.e., up to 3 to 4 weeks) that interferes with compliance and rehabilitation attempts. Hence, psychostimulants (i.e., dextroamphetamine, methylphenidate, pemoline) offer an attractive alternative for the treatment of depression among the medically ill.

Unfortunately, barriers (e.g., myths regarding addiction, abuse, and tolerance, and anorectic effects) to the prescription of psychostimulants by clinicians exist. Physicians distrust stimulants because of their checkered history; this distrust has led patients to resist taking stimulants. Moreover, because they are classified as a scheduled drug with a potential for abuse, their use has been limited to selected populations.

This article addresses the use of psychostimulants in a variety of illnesses and discusses the pharmacology, side effects, drug interactions, dosage guidelines, tolerance and abuse potential, and potential areas for future research.

Section snippets

CHEMISTRY AND PHARMACOLOGY OF THE PSYCHOSTIMULANTS

β-Phenylethylamine is the parent compound of sympathomimetic amines, including the psychostimulant amphetamine (Fig. 1). Substitutions on the aromatic ring, the α- and β-carbons, and the terminal amino group contribute to a variety of sympathomimetic compounds with a range of physiologic activities.51 In general, substitution on the α-carbon prolongs physiologic activity by inhibiting the oxidating potential of monoamine oxidase (MAO), and hydroxy substitution on the β-carbon decreases central

Patients with General Medical Illness

Although the first major review of amphetamine therapy was published in 1939, it was not until the mid- to late 1970s that their use for the depressed medically ill was advocated. At the 1978 annual meeting of the American Psychiatric Association, Dr. Thomas Hackett outlined 10 important indications for amphetamine use. In addition to their previously reported use in narcolepsy, as an antidote to amobarbital during the Amytal interview, for enhancement of verbal communication in psychotherapy,

DOSING OF PSYCHOSTIMULANTS

Recommended starting doses, peak doses, and dosage schedules are listed in Table 6. Because the half-life of MPD is 2 to 7 hours,21 most patients need at least twice-a-day dosing (at 8 am and 12 noon). We recommend starting with 5 mg at 8 am and observing how the patient does 1 hour after the first dose. We usually check the pulse and the blood pressure prior to and 1 hour after the first dose to determine if the patient shows evidence of sinus tachycardia or hypertension (pulse > 100

CONTRAINDICATIONS TO PSYCHOSTIMULANTS

Relative contraindications to the use of psychostimulants in the medically ill include: a history of hypersensitivity to stimulants; history of psychosis or tics; pregnancy; uncontrolled hypertension or arrhythmias; a history of abusing stimulants; or concomitant use of monoamine oxidase inhibitors (MAOIs) (even though there have been case reports describing the safe combination of MAOIs and psychostimulants with good success).33, 35

DRUG INTERACTIONS

The important interactions of psychostimulants with other drugs can be divided into four categories: (1) drug effects inhibited by psychostimulants, (2) drug effects potentiated by psychostimulants, (3) drugs that inhibit psychostimulant effects, and (4) drugs that potentiate psychostimulant effects (Table 7). Interference with hepatic metabolism, delayed absorption, intensified urinary excretion, and additive adrenergic effects are the mechanisms by which these interactions occur. Most of the

SIDE EFFECTS

Psychostimulants are capable of producing a range of central nervous system, cardiovascular, and GI disturbances that are generally dose-related and reversible (Table 8). Their use in the medically ill, however, has been associated with few adverse effects and they have been used safely even in the presence of underlying cardiovascular or central nervous system disease. Their comparative safety is probably a function of the low doses and brief courses of treatment used in the depressed

TOLERANCE, ABUSE, AND ADDICTION

All agents labeled as psychostimulants, central nervous stimulants, or amphetamine-based appetite suppressants have abuse potential. Their capacity to produce euphoria and a sense of well-being can lead to craving and compulsive use. In animals, a variety of different experimental techniques have demonstrated that the psychostimulants activate mesolimbic and mesocortical “pleasure pathways” in the brain.47 Electrical stimulation of these areas produces behavior similar to that elicited by

FUTURE DIRECTIONS FOR RESEARCH

Future directions for research include the following:

  • 1

    Placebo-controlled trials of stimulants for depression in the medically ill including patients with stroke, AIDS, Parkinson's disease, head injury, and cardiac problems.

  • 2

    Studies of stimulants should evaluate efficacy at 24 to 72 hours rather than after 1 to 2 weeks (which is the traditional period for follow-up in controlled clinical trials) to demonstrate quick onset of action.

  • 3

    Systematic long-term follow-up studies of medically ill

ACKNOWLEDGMENT

The authors wish to thank Theodore Stern, MD, for his helpful suggestions and critical review of the manuscript.

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