Dr. Howland is Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania.
The author has disclosed no potential conflicts of interest, financial or otherwise.
Address correspondence to Robert H. Howland, MD, Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, 3811 O’Hara Street, Pittsburgh, PA 15213; e-mail: HowlandRH@upmc.edu.
The brain reward system consists of extensive neural pathways that mediate reward behavior such as pleasure and motivation, and these pathways may be involved in the development of symptoms such as apathy, anhedonia, and cognitive dysfunction seen in patients with major depression (Naranjo, Tremblay, & Busto, 2001). These pathways are served primarily, although not exclusively, by the chemical neurotransmitter dopamine, suggesting a therapeutic role for drugs that influence dopamine activity. In this article, I will provide an overview of the use of dopaminergic and stimulant drugs for the treatment of depression.
The two main stimulant drug classes are amphetamine compounds and methylphenidate compounds. Drugs in each class are available in many different formulations. Amphetamine products are available as dextroamphetamine (Dexedrine®), amphetamine/dextroamphetamine (Adderall®), and lisdexamfetamine (Vyvanse®). Amphetamine is a sympathomimetic drug of the phenethylamine class. Sympathomimetic drugs mimic the effects of sympathetic nervous system neurotransmitters (e.g., epinephrine, norepinephrine [NE], and dopamine [DA]). Amphetamine is a racemate drug, and dextroamphetamine (d-amphetamine) is the d-enantiomer. Dextroamphetamine and levoamphetamine (l-amphetamine) have differential effects on the neurotransmitters DA and NE and on the metabolic enzyme monoamine oxidase, and their pharmacokinetic profiles are somewhat different. Levoamphetamine is not marketed separately but is present in small amounts in the amphetamine/dextroamphetamine combination products. Amphetamine has two main pharmacological actions. First, similar to many antidepressant drugs, it inhibits the neuronal reuptake of NE, DA, and to a lesser extent, serotonin (5HT). Second, it facilitates the neuronal release of NE, DA, and 5HT. Lisdexamfetamine is an inactive prodrug in which the enantiomer dextroamphetamine is chemically bonded to the amino acid enantiomer L-lysine. After oral ingestion, the bond is metabolically cleaved in the gut, and lisdexamfetamine is converted to L-lysine and to the pharmacologically active drug dextroamphetamine.
Methylphenidate, a piperidine class sympathomimetic drug that has some structural similarity to amphetamine, inhibits the neuronal reuptake of NE and DA. It also facilitates their neuronal release, although to a lesser extent than amphetamine, but does not have any clear effects on 5HT reuptake or release. Methylphenidate products are available as methylphenidate (Ritalin®, Concerta®, Metadate®, Methylin®), methylphenidate transdermal patch (Daytrana®), and dexmethylphenidate (Focalin®). Pemoline (Cylert®) is a sympathomimetic drug having pharmacological effects similar to methylphenidate, but it is no longer commercially available in the United States (withdrawn from the market because it was associated with liver toxicity).
Formulations of methylphenidate and amphetamine are approved by the U.S. Food and Drug Administration (FDA) for the treatment of attention-deficit/hyperactivity disorder (ADHD) and narcolepsy and are used for daytime somnolence in patients with sleep apnea. Before the advent of conventional antidepressant drugs, stimulant drugs were commonly used for the treatment of depression (Satel & Nelson, 1989). In animal models of depression, stimulant drugs have been shown to have antidepressant-like effects. In contemporary practice, they sometimes are used for treating depression in older adults (Hardy, 2009). They can also be added to antidepressant drugs to augment their clinical effects and treat adverse effects such as fatigue, apathy, and sexual dysfunction.
An open-label study found that adding pemoline or dextroamphetamine to monoamine oxidase inhibitor anti-depressant drugs was safe and effective for patients with treatment-resistant depression (TRD) (Fawcett, Kravitz, Zajecka, & Schaff, 1991). However, several more recent placebo-controlled studies failed to demonstrate a significant antidepressant benefit when methylphenidate was used to augment antidepressant medication (Patkar et al., 2006; Ravindran et al., 2008), and one placebo-controlled study did not find methylphenidate effective for treating antidepressant-associated sexual dysfunction (Pae et al., 2009). An unpublished exploratory study found that lisdexamfetamine augmentation was more efficacious than placebo augmentation for alleviating residual depressive symptoms in patients taking escitalopram (Lexapro®), although the results were not statistically significant (see http://clinicaltrials.gov, trial NCT00905424).
Possible adverse effects of methylphenidate and amphetamine drugs are nausea, anorexia, stomach pain, weight loss, dizziness, irritability, dysphoria, moodiness, agitation, anxiety, insomnia, nightmares, tachycardia, hypertension, and heart palpitations. Tolerance, dependence, and abuse are possible.
Atomoxetine (Strattera®) is an antidepressant drug that has a prominent effect on inhibiting NE reuptake and a relatively weaker effect on DA reuptake inhibition. However, it has relatively weak antidepressant effects and is not FDA approved for treating depression, but it is approved for the treatment of ADHD. A placebo-controlled study of atomoxetine augmentation for TRD found no benefit (Michelson et al., 2007), although the drug might be useful for treating fatigue associated with depression (Papakostas, Peterson, Burns, & Fava, 2006). Common adverse effects include dry mouth, nausea, headache, dizziness, abdominal pain, constipation, decreased appetite, weight loss, insomnia, and urinary retention.
The racemate drug modafinil (Provigil®), and its enantiomer R-modafinil (Nuvigil®), have a stimulating effect in the central nervous system, possibly by activating alpha-adrenergic and DA activity in discrete regions of the brain, but the effect is unlike that of methylphenidate or amphetamine. They are both FDA approved for the treatment of narcolepsy and excessive daytime sleepiness associated with sleep apnea. Modafinil is used as an alternative treatment for ADHD and is sometimes added to antidepressant drugs (typically serotonin reuptake inhibitor drugs) to augment their clinical effects and to treat certain adverse effects (e.g., apathy, fatigue, sexual dysfunction).
A pooled analysis of two placebo-controlled augmentation studies in patients with major depression found modafinil modestly effective for improving depression, sleepiness, and fatigue (Fava et al., 2007). A placebo-controlled augmentation study in patients with bipolar depression demonstrated significant antidepressant benefits (Frye et al., 2007). A small open-label study suggested possible efficacy for modafinil in seasonal affective disorder (Lundt, 2004). R-modafinil has not been investigated as an augmentation agent. Unlike methylphenidate or amphetamine, modafinil and R-modafinil are not prone to the development of tolerance, dependence, or abuse. Possible adverse effects include nausea, dizziness, headache, insomnia, and anxiety.
Dopamine-Releasing and Dopamine-Agonist Drugs
Dopamine-releasing and dopamine-agonist drugs are sometimes used to augment the effects of antidepressant agents and to relieve side effects such as apathy and sexual dysfunction. Amantadine (Symmetrel®), a closely related chemical analogue of the drug memantine (Namenda®), is an FDA-approved treatment for influenza (Type A), Parkinson’s disease, and drug-induced parkinsonian side effects. It increases DA activity by facilitating the presynaptic release of DA and possibly blocking the presynaptic reuptake of DA. Similar to memantine, it may also block activity at glutamate receptors. One open-label study found that amantadine was effective in augmenting the effects of antidepressant drugs in TRD (Stryjer et al., 2003). Another nonrandomized, parallel-group study found that imipramine plus amantadine was more effective than imipramine (Tofranil®) alone for patients with TRD (Rogóz et al., 2007). Possible adverse effects include dizziness, headache, nausea, loss of appetite, irritability, insomnia, speech dysarthria, ataxia, and impaired concentration. Rarely, seizures and psychosis can occur.
Bromocriptine (Parlodel®) is a postsynaptic DA receptor agonist that is FDA approved for the treatment of hyperprolactinemia and Parkinson’s disease. Pramipexole (Mirapex®) and ropinirole (Requip®) are also post-synaptic DA receptor agonist drugs. Both are FDA approved for treating Parkinson’s disease and restless legs syndrome.
A small open-label study found that adding bromocriptine to tricyclic anti-depressant drugs was effective for TRD (Inoue et al., 1996). A controlled study comparing pramipexole, fluoxetine (Prozac®), and placebo for major depression demonstrated that both active drugs were more effective than placebo (Corrigan, Denahan, Wright, Ragual, & Evans, 2000). Open-label studies of pramipexole and ropinirole also suggested that they may be effective when used to augment antidepressant medication in TRD (Cassano et al., 2004, 2005).
Possible adverse effects of dopamine-agonist drugs include nausea, vomiting, headache, orthostatic hypotension, and dizziness. Cardiac arrhythmias occur rarely. With prolonged use or in older adults, motor dyskinesias (similar to tardive dyskinesia) can develop. Confusion, psychosis, and mania can occur. Sudden irresistible sleep attacks can occur without warning.
Dopaminergic and stimulant drugs have potential utility as adjunctive treatments for depression. Although very few controlled studies have yet been conducted, several larger clinical trials are now underway investigating the use of lisdexamfetamine for major depression and bipolar depression. Nurses working in clinical practice should be aware of the off-label use of these drugs, including their potential side effects, in combination with standard antidepressant drugs.
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