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Should Amphetamines Be Added to SSRI Therapy to Enhance The 1-MINUTE CONSULT ONEONE MINUTE CONSULT BRIEF ANSWERS TO SPECIFIC CLINICAL Q: Should amphetamines be added to SSRI QUESTIONS therapy to enhance the antidepressant effect? VIVEK SINGH, MD Department of Psychiatry, Cleveland Clinic occurs because the two drugs work on different DONALD A. MALONE, JR, MD systems—amphetamine on the dopamine and Department of Psychiatry, Cleveland Clinic norepinephrine systems and SSRIs on the serotonin system. It has also been postulated IT IS DIFFICULT to make any definite that psychostimulants decrease the response A: conclusions about the role of psycho- latency—the lag time from when an SSRI is stimulants in enhancing the antide- started until a response can be observed— pressant effect of selective serotonin reuptake when given early in the course of treatment. inhibitors (SSRIs). Although anecdotal reports and case series have suggested that psy- ■ WHAT THE LITERATURE SHOWS chostimulants can augment the efficacy of SSRIs in patients with major depression, we Although the theory is promising, research have no data from prospective controlled tri- has not provided definitive proof that adding als. a psychostimulant to SSRI therapy is benefi- cial. We conducted a MEDLINE search of ■ PSYCHOSTIMULANTS AND DEPRESSION studies published between 1980 and 2000 and found only four that looked at this issue: The theory In the past, amphetamines were used more Cohen6 added dextroamphetamine to flu- extensively to treat depression than they are oxetine in three patients with anergic depres- is attractive, now.1 Physicians began to use them less after sion and found that it resolved their persistent but we have more-effective drugs were introduced, ie, tri- anergia. He suggested that amphetamine- cyclic antidepressants and monoamine oxi- induced enhancement of dopamine and nora- few data dase inhibitors.2 drenergic activity improves mood, decreases Selective serotonin reuptake inhibitors— fatigue, and increases psychomotor activity. the newest class of antidepressants—are effec- Metz and Shader7 described four patients tive in treating major depressive episodes. with treatment-refractory depression who However, major depression does not respond responded to a combination of fluoxetine and satisfactorily to an SSRI in 21% to 55% of pemoline. cases.3 Stoll et al5 found that adding methyl- Amphetamines are currently used to aug- phenidate to SSRI therapy rapidly resolved ment therapy with standard antidepressants symptoms in five patients with major depres- (tricyclics and monoamine oxidase inhibi- sion. tors).2,4 Ample evidence also suggests that Postolache et al,8 in a randomized, dou- they are effective when added to SSRIs in ble-blind, placebo-controlled, parallel-design patients with depression caused by a medical study, evaluated whether adding methyl- illness.5 Therefore, it seems logical to add phenidate to sertraline would decrease the amphetamine to an SSRI when a partial response latency. Response to therapy was response occurs. determined using the Hamilton Rating Scale Researchers assume that an additive effect for Depression—a 21-item, clinician-adminis- tered rating scale used to assess both the sever- ity of a patient’s depressive symptoms and This paper discusses treatment that is ”off label,” ie, not FDA-approved for the use under discussion. response to treatment. 748 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 68 • NUMBER 9 SEPTEMBER 2001 Downloaded from www.ccjm.org on September 29, 2021. For personal use only. All other uses require permission. The trial had to be stopped, however, ill, even if there is an initial response it is not after a preliminary analysis of the initial nine maintained. patients revealed that the therapy had not When treating patients with depression decreased their Hamilton Rating Scale scores caused by a medical illness, dextroampheta- or improved their global functioning. mine or methylphenidate can be used to aug- Therefore, despite the hint of a relation- ment antidepressant therapy. Dextroampheta- ship between improvement in depressive mine is started at a dose of 5 to 10 mg per day. symptoms and the addition of psychostimu- Methylphenidate can be started at a dose of 2.5 lants in three of these four studies, no firm to 5 mg twice a day. The daily maximum dosage conclusions can be drawn. We also have to of dextroamphetamine is usually 5 to 30 mg per wonder whether a placebo effect may be at day. The maximum dose of methylphenidate is work, whether the perceived antidepressant between 5 to 40 mg per day. effect may have been due to additional time To prevent insomnia, these drugs should on SSRIs, or whether the psychostimulants not be given after 3 PM. Because medically ill somehow increased the serum levels of the patients are particularly vulnerable to the SSRIs. multiple side effects of psychostimulants, these drugs should be used cautiously in this ■ SIDE EFFECTS patient population. OF PSYCHOSTIMULANTS ■ REFERENCES 1. Schatzberg AF, Cole JO. Manual of clinical psychopharma- The use of psychostimulants in general is con- cology. Washington, DC: American Psychiatric Press; troversial because of the potential for abuse 1991:247–259, 263–277. 5 2. Warneke L. Psychostimulants in psychiatry. Can J and risk of physical dependence. Psychiatry 1990; 35:3–10. Psychostimulants can also cause substan- 3. Davis JM, Wang Z, Janicak PG. A quantitative analysis of tial side effects. According to one report, sub- clinical drug trials for the treatment of affective disor- ders. Psychopharmacol Bull 1993; 29:175–181. jective side effects occur from most to least 4. Rosenberg PB, Ahmed I, Hurwitz S. Methylphenidate in often in the following order: insomnia, nau- depressed medically ill patients. J Clin Psychiatry 1991; sea, tremor, appetite change, palpitations, 52:263–267. Amphetamine blurred vision, dry mouth, constipation, and 5. Stoll Al, Pillay SS, Diamond L, et al. Methylphenidate augmentation of selective serotonin reuptake inhibitors: can be added dizziness.9 Patients may also experience objec- a case series. J Clin Psychiatry 1996; 57:72–76. tive side effects such as blood pressure 6. Cohen AJ. Treatment of anergic depression in to an SSRI for changes, dysrhythmias, and tremor.9 In addi- Hashimoto’s thyroiditis with fluoxetine and d-ampheta- mine. Depression 1993; 1:110–114. depression tion, confusion, exacerbation of preexisting 7. Metz A, Shader RI. Combination of fluoxetine with anxiety, agitation, hypomania, paranoid delu- pemoline in the treatment of major depressive disorder. caused by sions, and changes in sensorium can occur.9 Int Clin Psychopharmacol 1991; 6:93–96. 8. Postolache TT, Rosenthal RN, Hellerstein DJ, et al. Early medical illness augmentation of sertraline with methylphenidate. J Clin ■ AMPHETAMINES Psychiatry 1999; 60:2:123–124. 9. Satel SL, Nelson JC. Stimulants in the treatment of IN MEDICALLY ILL PATIENTS depression. A critical overview. J Clin Psychiatry 1989; 50:241–249. It is unknown why amphetamines help depres- ADDRESS: Donald A. Malone, Jr., MD, Department of sion in the medically ill but not in the non- Psychiatry, P68, The Cleveland Clinic Foundation, 9500 Euclid medically ill population. In the non-medically Avenue, Cleveland, OH 44195. CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 68 • NUMBER 9 SEPTEMBER 2001 749 Downloaded from www.ccjm.org on September 29, 2021. For personal use only. 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