A Review of Psychostimulants for Adults With Depression

Fed Pract. 2015 Apr; 32(Suppl 3): 30S–37S.

A Review of Psychostimulants for Adults With Low

Abstruse

A survey of medical literature suggests that for patients with depression who have not responded to other augmentation strategies, psychostimulants may offer improvements in mood, energy, and concentration.

Depression is a common status that significantly impairs social and occupational functioning. Many patients do not respond to start-line pharmacotherapies and are considered to take treatment-resistant low (TRD). These patients may benefit from augmentation of their antidepressant to reduce low. Multiple medications accept demonstrated various degrees of efficacy for augmentation, including psychostimulants. This article reviews studies of psychostimulants every bit augmentation agents for TRD and discusses risks, offers advice, and makes recommendations for clinicians who prescribe stimulants.

Groundwork

Major depressive disorder (MDD) is a common psychiatric condition that significantly impairs quality of life.one It is a recurrent illness, averaging 2 relapses per decade. The probability of recurrence increases with the number of depressive episodes.2,3 A patient who experiences major depressive episodes alternating with euthymia has unipolar depression; whereas ane who experiences major depressive episodes alternate with episodes of mania or hypomania has bipolar depression.4

Despite adequate dose and elapsing of pharmacotherapy, many individuals with unipolar or bipolar depression do not reach and sustain remission.5 Remission rates decrease and relapse rates increase with subsequent failed antidepressant trials.6 It is difficult to identify factors that predict handling resistance, merely one review of antidepressant studies institute that patients who did not demonstrate a response within 3 weeks of medication initiation were less likely to respond afterwards a longer duration.seven

Handling-resistant depression is usually, but not universally, defined equally lack of response later trials of ≥ two or more antidepressants with unlike mechanisms of activity for sufficient elapsing.5 This definition will be used here too. Other definitions accept proposed stages of TRD, but these require farther study to evaluate their reliability and predictive utility.8 Due to lack of consensus regarding the definition of TRD, it is not possible to determine the verbal prevalence of TRD.

Patients with TRD may do good from augmentation of their medication regimen. Augmentation with lithium has yielded conflicting results, and its efficacy with newer antidepressants is non well studied.9–12 Triiodothyronine, buspirone, and pindolol have demonstrated some efficacy when added to serotonin reuptake inhibitors (SRIs).10,12,thirteen Second-generation antipsychotic drugs, antidepressant drug combinations, omega-three fatty acids, Due south-adenosyl methionine (SAMe), and Fifty-methylfolate have demonstrated some efficacy in some studies also.12,14–23 In patients with depression who accept not responded to these strategies, psychostimulant augmentation may be appropriate.

METHODS

A literature search was conducted post-obit an algorithmic arroyo in the MEDLINE/PubMed database for studies in English from January 1985 to August 2014 of stimulants as augmenting agents for depression, using the Medical Subject Headings stimulant, depression, and augmentation, combined with an AND operator. The search was limited to adult humans and excluded case reports and letters, to identify studies with stronger evidence. Also excluded were studies using caffeine (to augment electroconvulsive therapy for low) and pemoline every bit the sole augmenting stimulant every bit well every bit studies of patients with comorbid mental wellness diagnoses and studies that initiated stimulants and antidepressants simultaneously to appraise antidepressant response.

This review organized results by stimulant rather than by low type, even though some studies used > ane stimulant or recruited patients with different types of depression. Although prevalence, prognosis, and monotherapy differ for unipolar and bipolar low, psychostimulants target similar symptoms, despite augmenting different monotherapies in unipolar and bipolar depression. Therefore, no distinction is made between assessing studies of stimulants for unipolar and bipolar depression.

RESULTS

A full of 70 articles were identified, and 31 studies met inclusion criteria (Figure). Of the studies included, 12 were double-bullheaded, placebo-controlled (DBPC) trials and 19 were retrospective chart reviews or open studies. Well-nigh studies evaluated depression, using validated scales, such as the Hamilton Low Rating Calibration, Montgomery-Asberg Depression Rating Calibration, Clinical Global Impressions of Severity, Inventory of Depressive Symptoms, Carroll Depression Rating Calibration, Global Assessment of Operation, Quick Inventory of Depressive Symptomatology, or the Psychiatric Symptom Assessment Scale. Study details are provided in Tables 1 to 4.

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PRISMA 2009 Flowchart74

Abbreviation: PRISMA, preferred reporting items for systematic reviews and meta-analyses.

Table 1

Studies of Dextroamphetamine and Lisdexamfetamine for Low

Written report	Type of Study	No.	Stimulant/Dose	Depression Type	Main Findings	Adverse Events
Feighner et al25	Retrospective nautical chart review	16	Dextroamphetamine five–20 mg/d or methylphenidate 10–15 mg/d	13 unipolar, three bipolar	9 were "very much" or "much" improved	Hypotension, irritability, nausea, insomnia; hypomania (in i)
Fawcett et al26	Prospective example series	32	Dextroamphetamine 7.v–40.0 mg/d	Unipolar and bipolar (non specified)	10 were "very much" or "much" improved	Memory damage, parkinsonism, weight gain; hypomania (in ane)
Masand et al28	Retrospective example serial	vii	Dextroamphetamine 10–30 mg/d; Methylphenidate x–30 mg/d	Unipolar MDD with or without persistent depressive disorder	All 7 reported improvement	None reported
Parker et al31	Prospective example series	50	Dexamphetamine xxx mg/d (max) or methylphenidate 60 mg/d (max) as adjunct or monotherapy	23 unipolar, 27 bipolar	eighteen patients reported no comeback or adverse events	Jittery, broken-hearted, headaches, nausea; mania (in 1)
Parker et al32	Prospective case series (extension study)	112	Dexamphetamine 15 mg/d; methylphenidate 25 mg/d as adjunct or monotherapy (mean doses)	61 unipolar, 51 bipolar	"very constructive" for 20% and "somewhat effective" for 50% of patients	Irritability, agitation, poor focus, tachycardia
Trivedi et al29	half dozen-wk DBPC	177	Lisdexamfetamine xx–fifty mg/d	Unipolar	Significant reduction on depression scale (MADRS) endpoints	Dry out rima oris, headache, anorexia, pharyngitis, insomnia
Madhoo et al30	9-wk DBPC	143	Lisdexamfetamine twenty–70 mg/d	Unipolar	Improvement in executive part and rest depressive symptoms	Anorexia, headache, dry mouth, insomnia, irritability

Table ii

Studies of Methylphenidate for Low

Study	Type of Study	No.	Stimulant/Dose	Depression Type	Master Findings	Adverse Events
Stoll et al27	Prospective case series	5	Methylphenidate ten–40 mg/d	Unipolar MDD	All 5 self-reported improvement of depression	None reported, no evidence of misuse
Lydon et al33	Retrospective chart review	sixteen	Methylphenidate 5.0–forty.0 mg/d (average sixteen.three mg/d)	Bipolar	Improved concentration (viii); decreased depression (4); interest, energy, motivation, slumber, appetite	Irritability, agitation, anxiety, insomnia, ambition, headache, tachycardia, tremor; no mania or hypomania
Carlson et al34	Retrospective chart review serial	8	Methylphenidate xx–forty mg/d; dextroamphetamine x–60 mg/d	Bipolar	6 of eight patients reported "much" or "very much" improved on Clinical Global Impressions Scale	Perioral twitch (in 1) or balmy anxiety (in 1); no mania, hypomania, or misuse
El-Mallakh35	12-wk prospective study	14	Methylphenidate ten–twenty mg/d with mood stabilizer	Bipolar	Moderate decrease on ane depression calibration (HDRS), meaning decrease on another (PSAS)	Mania (in 1), agitation, or anxiety
Ravindran et al36	5-wk DBPC	145	OROS methylphenidate 18–54 mg/d	Unipolar	No statistical deviation between groups on depression measures	Headache, gastrointesinal distress, pharyngitis, dry mouth, fatigue, anxiety, insomnia
Patkar et al37	four-wk DBPC	60	OROS methylphenidate eighteen–54 mg/d	Unipolar	No statistical difference betwixt groups on depression measures	Anorexia, nausea, insomnia, headache, feet, tremor

Tabular array 4

Studies of Armodafinil and Atomoxetine for Low

Written report	Type of Study	No.	Stimulant/Dose	Low Blazon	Main Findings	Adverse Events
Calabrese et al56	8-wk/DBPC	257	Armodafinil 150 mg/d	Bipolar	Significant reduction in low	Headache, indisposition, diarrhea
Calabrese et al57	8-wk/DBPC	433	Armodafinil 150 mg/d	Bipolar	Significant reduction in depression	Headache, nausea, diarrhea, dry mouth
Carpenter et al59	iv-mo prospective	fifteen	Atomoxetine 40 mg/d	12 unipolar, i bipolar, 2 unspecified	Statistically meaning improvement in depression	Nausea, vomiting; no change in pulse or blood pressure
Papakostas et al60	Retrospective chart review	12	Atomoxetine 43 mg/d (boilerplate dose)	Unipolar MDD	Improvement in fatigue and depression scales but not overall functioning	Insomnia, nausea, feet, dry mouth
Michelson et al61	viii-wk/DBPC	146	Atomoxetine 40–120 mg/d	Unipolar MDD	No difference in low between treatment and placebo groups	Dry mouth, constipation, insomnia, sweating, fatigue

Dextroamphetamine and Methylphenidate

Dextroamphetamine and methylphenidate are indicated for the treatment of attention-deficit/hyperactivity disorder (ADHD) and exert their effects by inhibiting uptake of norepinephrine and dopamine.24 In one nautical chart review, patients received dextroamphetamine or methylphenidate augmentation of monoamine oxidase inhibitors (MAOIs) alone or with concurrent tricyclic antidepressants; the majority reported decreased low.25 In an open up-characterization trial, dextroamphetamine was titrated to efficacy in patients who were receiving an MAOI with or without pemoline.26 Virtually lxxx% of patients reported long-lasting improvement in depression. In an open-label trial, all patients reported decreased depression when methylphenidate was added to SRIs; however, no scales were used.27

In a case series, patients with both major depression and persistent depressive disorder (dysthymia) experienced a substantial, quick, and sustained response to dextroamphetamine or methylphenidate augmentation.28 Addition of lisdexamfetamine significantly reduced depressive symptoms in individuals with inadequate response to escitalopram.29 Patients with full or fractional remission of depression noted improved executive part and residual depressive symptoms later lisdexamfetamine was added to SRI monotherapy.thirty In a trial in which patients received dexamphetamine or methylphenidate as monotherapy or augmentation, thirty% to 34% of patients reported mood improvement, but 36% reported no comeback.31 In an extension study, low-dose psychostimulants quickly macerated affective.32

Methylphenidate was safe and effective in patients with bipolar depression receiving treatment for 1 to 5 years; 44% evidenced pregnant improvement.33 When offered to patients with bipolar depression, patients receiving methylphenidate or dextroamphetamine reported less depression or sedation and did non develop tolerance, mania, or misuse.34 A instance series ended that methylphenidate addition to mood stabilizers was mostly effective and safety.35

However, not all preparations of methylphenidate take demonstrated efficacy. In 1 study, osmotic controlled-release oral system (OROS) methylphenidate improved aloofness and fatigue but not overall depression.36 Although OROS methylphenidate similarly failed to demonstrate statistically pregnant efficacy in another study, more responders were documented in the treatment group.37

Table 3

Studies of Modafinil for Depression

Written report	Type of Study	No.	Stimulant/Dose	Depression Blazon	Primary Findings	Agin Events
Menza et al42	Retrospective chart review	vii	Modafinil 100–200 mg/d	4 unipolar, 3 bipolar	5 of 7 patients with 50% subtract in depression	None observed
Markovitz et al43	Open-label instance series	27	Modafinil 200–400 mg/d	23 unipolar, 4 bipolar	Increment of x points of boilerplate Global Assessment of Functioning	Headache
Fernandes et al44	Retrospective chart review	2	Modafinil	Bipolar	Decreased hypersomnia	None observed
Nasr45	Prospective example series	78	Modafinil 100–400 mg/d 100–800 mg/d	59 unipolar, 13 bipolar, 6 "other"	Significant improvement globally and in depression, attention, and knowledge	None observed
DeBattista et al46	Prospective open-label trial	35	Modafinil 100–400 mg/d	Unipolar MDD	Meaning and rapid improvement on all measures of depression and fatigue starting at 2 wks	None reported
Nasr47	Retrospective chart review	191	Modafinil 230 mg/d (bipolar) and 287 mg/d (unipolar) (hateful)	118 unipolar, 64 bipolar, 9 "other"	No prove of mood switch, tolerance or misuse	None noted
DeBattista et al48	6-wk DBPC	136	Modafinil 100–400 mg/d	Unipolar	Improved wakefulness and mood short-term	Headache, feet, insomnia, infection
Frye et al49	six-wk DBPC	85	Modafinil 100–200 mg/d	Bipolar	Pregnant subtract in depression; overall global improvement	Headache, infection, hypomania, indisposition, tachycardia
Thase et al51	12-wk, open-label extension study	254	Modafinil 100–400 mg/d (mean 268 mg/d)	Unipolar	Reduced fatigue and improved mood	Headache, nausea, dizziness
Fava et al52	8-wk DBPC	158	Modafinil 200 mg/d	Unipolar	Significant improvement overall and in fatigue and low	Headache, nausea, dizziness, dry mouth, pharyngitis
Abolfazli et al53	6-wk DBPC	46	Modafinil 400 mg/d	Unipolar MDD	Significant improvement in depression	Anxiety, indisposition, decreased ambition, headache
Rasmussen et al54	8-mo open up-label study	21	Modafinil 100.0–400.0 mg/d, average dose 190.5 mg/d	MDD (unipolar and bipolar non specified)	All patients reported ≥ 50% reduction on hypersomnolence; 43% reported ≥ 50% improvement in low	Minor headache
Dunlop et al55	6-wk DBPC	73	Modafinil 100–200 mg/d	Unipolar MDD	Improved fatigue just not depression; trial terminated prematurely	Headache, nausea, diarrhea, sinusitis

Although this review focuses on stimulants as augmenting agents in patients with depression, it is worth noting the express number of studies evaluating stimulants' effect on low in patients with traumatic brain injury. This observation is of business organization, as these conditions are often comorbid in returning veterans. One study noted that methylphenidate was an constructive monotherapy for depression; whereas some other study found that methylphenidate monotherapy reduced depression as well as sertraline, was improve tolerated, and improved fatigue and cognition.38,39

Modafinil and Armodafinil

Modafinil and armodafinil (the R-enantiomer of modafinil) are indicated for improving wakefulness in individuals with narcolepsy, obstructive sleep apnea, and shift work sleep disorder past modulating glutamate, gamma amino-butyric acrid, and histamine.40,41 Although they increase extracellular dopamine concentrations, they do not crusade an increase in dopamine release and may accept less misuse potential than that of dextroamphetamine and methylphenidate.40,41 In a study of 7 patients with unipolar or bipolar depression, all patients accomplished full or partial remission with minimal agin effects (AEs).42 In a prospective written report, 41% of patients reported just mild depression or full remission with modafinil augmentation.43

Multiple trials and a pooled analysis noted decreased depression and fatigue and improved noesis in patients receiving modafinil augmentation compared with mood stabilizers or antidepressants.44–49 Modafinil is a useful adjunct for partial responders to SRIs, resulting in rapid mood improvement and decreased fatigue.50–54 All the same, in one written report, modafinil did not demonstrate efficacy compared with placebo. This issue was attributed to premature study termination afterward 2 modafinil-treated patients developed suicidal ideation.55 A mail hoc analysis institute no difference in frequency of suicidal ideation between groups.

Two DBPC studies evaluated armodafinil in patients with bipolar low. In both studies information technology was added to a mood-stabilizing agent (lithium, valproate, aripiprazole, olanzapine, lamotrigine, risperidone, or ziprasidone), and patients receiving armodafinil reported meaning reductions in depression.56,57

Atomoxetine

Atomoxetine is a norepinephrine reuptake inhibitor indicated for the handling of ADHD and is considered to take no misuse potential due to lack of dopamine modulation. 58 In ane study, xv patients received atomoxetine added to their antidepressant, and 60% experienced significant symptom reduction.59 A nautical chart review noted decreases in fatigue and depression when atomoxetine was added to an SRI, mirtazapine, or amitriptyline.lx Even so, in a DBPC trial, atomoxetine did non lead to significant changes in low.61

DISCUSSION

There is a limited amount of loftier-quality evidence to support psychostimulant augmentation, as noted by the relatively few DBPC trials, nigh of short duration. The evidence supports their efficacy primarily for unipolar depression, as 14 studies evaluated patients with unipolar low, whereas only 7 studies evaluated patients with bipolar depression. The remaining studies recruited patients with both low types. Collectively, modafinil and armodafinil have the most evidence in DBPC trials.

There are relatively few DBPC trials with high ability and sufficient duration for dextroamphetamine and methylphenidate preparations. This discovery is surprising, because the duration that these medications take been bachelor. However, several chart reviews and open-characterization trials provided some show to back up their use in patients without a history of substance misuse or cardiac atmospheric condition.62 Osmotic controlled-release oral system methylphenidate seems to exist ineffective, and the efficacy of atomoxetine for augmentation is uncertain.

Precautions

Prescribing physicians who offer stimulants should consider potential AEs, such as psychosis, anorexia, anxiety, insomnia, mood changes (eg, acrimony), misuse, habit, mania, and cardiovascular issues. Psychostimulants have been implicated in precipitating psychosis. 63,64 However, in a 12-calendar month study of 250 adults with ADHD, 73 reported AEs, and just 31 discontinued the stimulant. Agin effects leading to discontinuation included mood instability (n = 7), agitation (n = six), irritability (northward = 4), or decreased appetite (due north = 4).65

Although associated with the risks of anorexia and insomnia in patients with ADHD, methylphenidate chop-chop improved daytime sleepiness and mood, and—paradoxically—appetite and nighttime sleep in medically ill elderly patients with depression.66 Misuse or abuse of methylphenidate and dextroamphetamine were noted in 23% of patients referred for substance misuse.67 Nonetheless, niggling prove exists that these drugs possess meaning misuse potential in patients taking them as prescribed. As a prodrug, lisdexamfetamine is hypothesized to have less abuse potential compared with dextroamphetamine and methylphenidate, just it carries the same prescribing and monitoring precautions.68 Risks related to stimulant usage extend to manic symptoms.69 Patients with bipolar disorder should not receive stimulants if they accept a history of stimulant-induced mania, rapid cycling, or psychosis.70

Long-term cardiovascular safety data exist for dextroamphetamine and methylphenidate but are limited or unavailable for modafinil, armodafinil, and atomoxetine. A retrospective cohort study found no pregnant increase in the number of cardiac events in patients receiving dextroamphetamine, methylphenidate, or atomoxetine for an average of 1 yr compared with controls.71 Another cohort study of > 44,000 patients plant that initiation of methylphenidate was associated with increased chance of sudden decease or arrhythmia, just the risk was attributed to an unmeasured confounding factor, as the authors found a negative correlation between methylphenidate dose and all cardiovascular events.72

Recent practice guidelines recommend that before prescribing stimulants, clinicians should perform a physical examination (including heart and lung auscultation), obtain vital signs and top and weight, and asking an electrocardiogram in instance of abnormal findings on a cardiovascular test or in instance of a personal or family unit history of heart affliction. Before offering atomoxetine, clinicians should evaluate the patient for a history of liver disease (and check liver function studies in case of a positive history). Clinicians should also appraise risk of cocky-impairment prior to initiating psychostimulant therapy.73 Throughout treatment, clinicians should evaluate the patient for changes in blood pressure, pulse, weight or mood, equally well as the evolution of dependence or misuse. Urine toxicology testing is recommended for dextroamphetamine and methylphenidate to screen for adherence and diversion.

Limitations

Using only PubMed and MEDLINE databases limited the search to articles published in English after 1985, excluding letters and case reports to identify studies with higher evidence (the studies were not weighted based on study blueprint). In addition, the studies had certain limitations. These include a limited number of DBPC trials, nearly were of short duration. Information technology is also difficult to compare studies due to various rating scales used and concurrent medication regimens of study subjects. These limitations raise questions surrounding the long-term efficacy of stimulants, and there is no consensus for how long a stimulant should be continued if beneficial. Longer, higher-powered, DBPC trials are warranted to determine long-term efficacy and safe of stimulant augmentation.62

Conclusion

For patients with depression who have not responded to other augmentation strategies, psychostimulants may be offered to improve mood, energy, and concentration. For clinicians considering stimulant augmentation, modafinil and armodafinil are reasonable choices given their efficacy in double-blind, placebo-controlled trials and lower risk of misuse. Dextroamphetamine (specially lisdexamphetamine) and methylphenidate may exist appropriate for patients who have non benefited from or tolerated modafinil or armodafinil, provided these patients do non have a medical history of cardiac disease or current substance use.

Osmotic controlled-release oral system methylphenidate seems to exist ineffective as an augmenting agent. The efficacy of atomoxetine for augmentation is questionable, but atomoxetine could be offered if other stimulants were contraindicated, ineffective, or poorly tolerated. Both OROS methylphenidate and atomoxetine should be evaluated in additional trials before they can be recommended equally augmentation therapies. Sure psychostimulants may exist appropriate and reasonable adjunctive pharmacotherapies for patients with unipolar or bipolar depression who have failed other augmentation strategies, for patients who have significant fatigue or cognitive complaints, or for elderly patients with melancholic or somatic features of depression.

Acknowledgements

The authors thank Maureen Humphrey-Shelton and Kathy Thomas for their help in obtaining references.

Footnotes

Author disclosures

The authors report no actual or potential conflicts of involvement with regard to this commodity.

Disclaimer

The opinions expressed herein are those of the authors and do not necessarily reverberate those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing data for specific drugs or drug combinations— including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

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