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The Use of Stimulants in Psychiatric Practice

with history of severe agitation, highly anxious states, and impulsiveness and to keep sedative hypnotic dosages within accepted parameters.

BIBLIOGRAPHY
1. Bunney WE Jr, Azarnoff DL, et al: Report of the Institute of Medicine Committee on the Efficacy and Safety of Halcion. Arch Gen Psychiatry 56:349-352, 1999. 2. Greenblatt DI, Harmatz JS, von Moltke LL, et al: Comparative kinetics and dynamics of zaleplon, zolpidem, and placebo. Clin Pha-macol Ther 64(5):553-561, 1998. 3. Kryger M, Roth T. Dement WD (eds): Principles and Practice of Sleep Medicine, 3rd ed. Philadelphia, W.B. Saunders, 1999. 4. Lob0 BL, Greene WL: Zolpidem: Distinct from triazolam? Ann Pharmacother 3 1(5):625-632, 1997. 5. Mendelson WB: Efficacy of melatonin as a hypnotic agent. J Biol Rhythms 12(6):651-656, 1997. 6. National Institute of Mental Health, National Institutes of Health: Drugs and Insomnia. Consensus Development Conference Summary, vol4, no 10. Bethesda, MD, U S . Department of Health and Human Services, 1984. 7. Nolen TM: Sedative effects of antihistamines: Safety, performance, learning, and quality of life. Clin Ther 19(1):39-55, 1997. 8. Poceta JS, Mitler MM: Sleep Disorders: Diagnosis and Treatment. Totowa, NJ, Humana Press, 1998. 9. Reite ML, Nagel KE, Ruddy JR: Concise Guide to the Evaluation and Management of Sleep Disorders. Washington, DC, American Psychiatric Press, 1997. 10. Wagner J , Wagner ML, Hening WA: Beyond benzodiazepines: Alternative pharmacologic agents for the treatment of insomnia. Ann Pharmacother 32(6):680-691, 1998.

52. THE USE OF STIMULANTS IN PSYCHIATRIC PRACTICE

Hubert H. T h o ~ l a s o Ju., ~ , M.D.
1. List the common stimulants prescribed in psychiatric practice. Trade Name Generic Name Dexedrine; Dextrostat Dextroamphetamine Dextroamphetamine/amphetamine Adderall (mixture) Ritalin; Ritalin SR; Methylphenidate Metadate; Metadate ER Provigil Modafinil

Dose Range 5-60 mg/day 5-60 mg/day

5-60 mg/day

100400 mg/day

2. Describe the physiologic effects of stimulants. Stimulants increase catecholaminergic activity in the brain through inhibition of monoamine oxidase (MAO), blockade of neuronal catecholamine reuptake, and direct release of catecholamine from nerve terminals. Serotonin (5HT) activity at the neuronal level also is altered. The resultant physiologic state is characterized on electroencephalography (EEG) by increased power, especially in the alpha range. This finding is related to the clinical state of arousal associated with the use of stimulants. Patients taking stimulants typically report activation, increased motivation, improved mood, and even euphoria (which may be followed by a dysphoric crash when catecholamine stores are depleted in the brain), suppression of drowsiness, and decreased need for sleep. Blood pressure and heart rate may be increased, and appetite suppression is common. Among the unpleasant physiologic effects of stimulants are increased sweating, restlessness and agitation, and stereotypic movements such as teeth grinding, jaw-clenching, and skin picking. Sexual functioning may be impaired, with decreased libido in both men and women, inability to maintain an erection in men, and anorgasmia in women.

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3. What are the common uses of stimulants in psychiatric practice?

The most common use of stimulants in psychiatric practice is in the treatment of attention deficithyperactivity disorder (ADHD) in children and occasionally adults. (ADHD is common in children, but rare in adults). The Food and Drug Administration (FDA) sanctions the use of stimulants in this disorder. Also approved by the FDA is the use of stimulants to treat narcolepsy, a rare disorder in which the sufferer is plagued by sleep attacks. Modafinil is specifically approved for narcolepsy. Important uses of stimulants beyond those approved by the FDA center on the treatment of mood disorders and amotivational states. Stimulants may be added to a partially effective antidepressant regimen to augment the antidepressant action (see Chapters 47 and 49) when it is impractical to increase the antidepressant dose, either because of adverse effects or because the maximal dose already has been reached without sufficient improvement. Amotivational states (which may or may not be tied to depression) may respond acutely to the use of stimulants. Such states include medically compromised patients who are not participating actively in treatment and therefore are at risk of further deterioration of functioning. The typical scenario involves elderly persons, persons who are having difficulty with weaning from a ventilator, patients infected with the human immunodeficiency virus (HIV), poststroke victims or postoperative neurosurgical patients, and terminally ill patients. Behavioral control and cognition have improved with stimulant treatment in chronic closed-head-injury patients. Clinical Pearl: Using a stimulant (5 mg of dextroamphetamine) helps to differentiate between depressed and demented patients. Depressed patients are likely to respond with improved mood, cognition, and alertness, whereas demented patients may show increased alertness but worsened cognition.

4. What are inappropriate uses of stimulants? Stimulants are not effective as the primary treatment for depression. Additionally, stimulants should not be used to relieve normal fatigue states. In general, weight control and appetite suppression are not clinically appropriate uses for stimulants because of lack of efficacy over time and risk of adverse effects. Behaviorally based treatments are better than stimulants for weight control. 5. List and discuss some of the common problems associated with prescription of stimulants. Tolerance. The sympathomimetic effects of stimulants diminish quickly at a steady dose. Thus persons using stimulants to produce euphoria, appetite suppression, energy, and wakefulness become quickly disappointed and seek to increase the dose to achieve the former level of stimulation. Of interest, tolerance does not develop to the therapeutic benefit of stimulants in ADHD, or to their antidepressant effects when used to augment treatment of depression, or in medically ill patients maintained on stimulants for amotivational states. Abuse. Stimulants have been extensively abused in the past because they are known to produce euphoria, energy, and wakefulness. An historically important form of stimulant abuse occurred during World War 11. Allied and Axis forces used amphetamine extensively. Japanese fighter pilots, on suicide missions in the Pacific, used amphetamine. Postwar Japan experienced an epidemic of amphetamine abuse when large stockpiles of amphetamine from the military were placed on the open market. The potential for abuse has caused stimulants to become heavily regulated in the United States. Adverse effects. Common or important stimulant-induced side effects include: Increased heart rate and blood pressure Anxiety Imtability Palpitations Tics and other involuntary movements Insomnia Dysphoria (teeth grindingljaw clenching) Transient growth suppression in children Emotional lability Decreased appetite Paranoia

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The Use o f Stimulants in Psychiatric Practice

Psychological dependence Hallucinations Physical dependence Psychosis Exacerbation of other illnesses such as glaucoma, hypertension, anxiety disorders, psychotic disorders, and seizure disorders Drug-drug interactions. Stimulants may decrease metabolism (and thus increase plasma level) of certain drugs: Tricyclic/tetracyclic antidepressants Phenobarbital Warfarin (Coumadin) Phenytoin (Dilantin) Primidone (Mysoline) Phenylbutazone (Butazolidin) Use stimulants with extreme caution in the presence of M A 0 inhibitors because of the possibility of a hypertensive crisis. In addition, exercise extreme caution when prescribing stimulants to patients with bipolar affective disorder, as these compounds may induce mania or rapid-cycling.

6. Summarize governmental regulation of stimulants. All stimulants (except modafinil, which has a schedule IV designation) are classified by the U.S. Drug Enforcement Agency (DEA) as schedule 11, along with certain narcotics. Additional regulations may vary from state to state, including the use of triplicate prescriptions for stimulants (one copy is filed with a state governmental agency). A proper state medical license and DEA certification are required for physicians to prescribe stimulants. Internationally there is much variability in the regulation of stimulants. Sweden has banned stimulants, whereas they are available without prescription in other countries. 7. Summarize practical information about prescribing stimulants.

Prescription of Stimulants *
DEXEDRINE RITALINMETADATE PROVIGIL ADDERALL

How supplied (Tablets)

5 , 10 mg Oral suspension: 5 mglml Sustained release: 5, 10, and 15 mg Cardiac, liver, and renal function None

10 and 20 mg

100,200 mg

5 , 10, 20, and 30 mg

Pretreatment evaluation Concurrent monitoring Starting dose (mg) Adults Children Increase dose weekly by Daily schedule

Cardiac, liver, and renal function None

Cardiac, liver, and renal function None

Cardiac, liver, and renal function None

2-5- 10 2-5 (3-5 yrs) 5 (6 yrs and older)

5 mg

5-10 5 5-10 mg Two to three times daily except longer acting form (once or twice daily)
60 mg

100-200 mg
No data in chil-

5-10 5
5-10

dren under 16
100 mg

Twice daily divided dose except in sustained release form (once daily)
60 mg

Once daily in AM

Twice or three times daily

Maximal recommended dose

400 mg

60 mg

* There is no indication for the use of stimulants during pregnancy. Dextroamphetamine (Dexedrine) and
methylphenidate (Ritalin) pass into breast milk.

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28 1

8. What are useful strategies for managing common stimulant-inducedadverse effects?

Management of Common Stimulant-Induced Adverse Effects in Attention Deficit/Hyperactivity Disorder
ADVERSE EFFECTS MANAGEMENT

Anorexia, nausea, weight loss Insomnia, nightmares

Administer stimulant with meals. Use caloric-enhanced supplements. Discourage forcing meals. Administer stimulants earlier in day. Change to short-acting preparations. Discontinue afternoon or evening dosing. Consider adjunctive treatment (e.g., antihistamines, clonidine, antidepressants). Monitor blood pressure. Encourage fluid intake. Change to long-acting form. Overlap stimulant dosing. Change to long-acting preparation or combine long- and shortacting preparations. Consider adjunctive or alternative treatment (e.g., clonidine, antidepressants). Assess timing of phenomena (during peak or withdrawal phase). Evaluate comorbid symptoms. Reduce dose. Consider adjunctive or alternative treatment (e.g., lithium, antidepressants, anticonvulsants).

Dizziness

Rebound phenomenon

Irritability

Growth impairment Dysphoria, moodiness, and agitation

Attempt weekend and vacation holidays. If severe, consider nonstimulant treatment. Consider comorbid diagnosis (e.g., mood disorder) Reduce dose or change to long-acting preparation. Consider adjunctive or alternative treatment (e.g., lithium, anticonvulsants, antidepressants). Avoid citric and ascorbic acid for 1 hour prior to the stimulant dose.

Poor or variable absorption

From Wilens TE, Biederman J: The stimulants. In Shaffer D (ed): Pediatric Psychopharmacology: The Psychiatric Clinics of North America. Philadelphia,W. B. Saunders, 1992, with permission.

BI BUOCRAPHY
1. Arieti S (ed): American Handbook of Psychiatry, 2nd ed. New York, Basic Books, 1986. 2. Evans RW, Gualtieri CT, Patterson D: Treatment of chronic closed head injury with psychostimulant drugs: A controlled case study and an appropriate evaluation procedure. J Nerv Mental Dis 175:106-110, 1987. 3. Femandez F, Levy JK: Psychopharmacologyin HIV spectrum disorders. Psychiatr Clin North Am 17:135148, 1994. 4. Gilberg C, et al: Long-term stimulant treatment of children with attention-deficit hyperactivity disorder symptoms: A randomized, double-blind,placebo-controlled trial. Arch Gen Psychiatry 543577864. 1997. 5 . Goodwin K, Jamison KR: Manic Depressive Illness. New York, Oxford Press, 1990. 6. Greenhill LL, et al: Medication treatment strategies in the MTA: Relevance to clinicians and researchers. J Am Acad Child Adolesc Psychiatry 35:1304-1313, 1996. 7. Hales RE, Yudofsky SC: Textbook of Neuropsychiatry. Washington, DC, American Psychiatric Press, 1987. 8. Kaplan HI, Sadock BJ: Pocket Handbook of Psychiatric Drug Treatment. Baltimore, Williams & Wilkins, 1993. 9. Kaplan HI, Sadock BJ: Comprehensive Textbook of Psychiatry, 6th ed. Baltimore, Williams & Wilkins, 1995. 10. Massie MJ, Shakin EJ: Management of depression and anxiety in cancer patients. In Breithart W, Holland JC (eds): Psychiatric Aspects of Symptom Management in Cancer Patients. Washington, DC, American Psychiatric Association, 1994, pp 1-21.

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Understanding Medication Interactions

11. Pickett P, Masand P, Murray GB: Psychostimulant treatment of geriatric depression disorders secondary to medical illness. J Geriatr Psychiatry Neurol 3(3):146-151, 1990. 12. Spencer T, et al: Pharmacotherapy of attention-deficit hyperactivity disorder across the life cycle. J Am Acad

Child Adolesc Psychiatry 35:409-432, 1996. 13. Woods SW, Tesar GE, Murray GB, Cassem NH: Psychostimulant treatment of depressive disorders secondary to medical illness. J Clin Psychiatry 47:12-15, 1986.

53 . UNDERSTANDING MEDICATION INTERACTIONS

Dee Opp, R.Ph., BCPP,and Lyle Laird, Phccv~zD, BCPP

1. Why are drug interactions important to consider? To maximize therapeutic outcome and minimize adverse side effects, a prescriber needs to understand how a drug works, how it is metabolized, and what side effects are common with the use of the medication. When you consider a new medication for use, you must know how it will interact both dynamically and kinetically with other medications. For example, if a patient is currently on clonidine for hypertension, and a tricyclic antidepressant (TCA) is being considered for therapy, the prescriber should know that the TCA could antagonize the alpha-2 agonist property of the clonidine and negate its antihypertensive effects. This is an example of a pharmacodynamic interaction. Thus, it is important to have an understanding of the mechanisms of action of medications to determine if one is likely to antagonize or block the therapeutic effect of another. In many therapeutic regimens, physicians are faced with using more than one agent to treat or ameliorate symptoms. All combinations need to be assessed for the presence of both kinetic and dynamic interactions. 2. What are the mechanisms of psychotropic medication metabolism? Most of the psychotropic medications are metabolized by a process known as phase I metabolism. This type of metabolism is carried out hepatically by a group of enzymes known as the cytochrome P450 (CYP450) mixed oxidase system. CYP450 enzymes break down the medications into more water-soluble metabolites, which then are more easily excreted into the urine and eliminated from the body. In addition, phase I1 metabolism involves another group of enzymes in the liver. This system primarily results in glucuronidation of drugs, which also allows them to be excreted in the urine. A clinically important example is the interaction between the anticonvulsants, lamotrigine and valproic acid. When these two medications are used together, valproic acid inhibits the phase 11 process of glucuronidation, causing up to a 50% decrease in lamotrigines clearance and a significant increase in its half-life. This effect on the pharmacokinetic parameters of lamotrigine can increase blood levels and, hence, side effects (most significantly, increasing the risk of StevenJohnsons syndrome).

3. Are there other ways medications interact beside via metabolism in the liver?
Medications can interact through multiple mechanisms, and all concurrently. The difficult task is to evaluate which one will influence the success of drug treatment the most. There are two main types of drug interactions: pharmacokineticand pharmacodynamic.Pharmacokinetic interactions involve how one drug influences the normal movement of another drug in the body. For example, one medication may inhibit the absorption of another. Ascorbic acid inhibits the absorption of amphetamines and therefore decreases their effectiveness in the treatment of attention deficit hyperactivity disorder. Another type of interaction is how one medication may influence the