Conditions: Major Depressive Disorder
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 41
Healthy volunteers: no

Brief summary:
In this Phase 4 trial we will study the safety, tolerability and efficacy of mixed salts amphetamine (MSA), trade name Adderall, augmentation of antidepressant therapy for Major Depressive Disorder (MDD) in depressed outpatient adults who are taking an antidepressant but have not had complete resolution of their symptoms.

Detailed description:
Forty adult outpatients with MDD who failed at least one adequate trial of antidepressant monotherapy will be consented in a 63-day, cross-sequential, multicenter study comprising two treatment phases of 21 days each. The time frame from consent to baseline is 7 days. Patients will receive placebo or MSA in Phase 1, and in Phase 2, participants will receive MSA. There will also be a two-week follow up visit after the completion of Phase 2.

We hypothesize that MSA will be safe and well tolerated, and will improve the patient's response to their antidepressant and provide superior symptom relief to antidepressant alone. The primary outcome measure is the Massachusetts General Hospital Cognitive-Physical Function Questionnaire (MGH-CPFQ).

Arms:
arm 1: Phase I (3 weeks) placebo adjunctive to Anti-Depressant Therapy (ADT). The total daily dosing of the concurrent ADT will be as follow: escitalopram 10-40 mg; Fluoxetine 20-80 mg; paroxetine controlled release (CR) 25-100 mg (paroxetine 20-80 mg may be substituted if paroxetine CR is not available); sertraline 100-400 mg; venlafaxine extended release (XR) 150-600 mg; desvenlafaxine 50-200 mg; citalopram 20-80 mg; or duloxetine 60-180 mg; buproprion 150-450 mg; mirtazapine 15-45 mg, tricyclics (standard dosing, individually per label instructions).

Phase II (3 weeks) mixed salts amphetamine adjunctive to ADT (as in Phase I). arm 2: Phase I (3 weeks) mixed salts amphetamine adjunctive to Anti-Depressant Therapy (ADT). The total daily dosing of the concurrent ADT will be as follow: escitalopram 10-40 mg; Fluoxetine 20-80 mg; paroxetine controlled release (CR) 25-100 mg (paroxetine 20-80 mg may be substituted if paroxetine CR is not available); sertraline 100-400 mg; venlafaxine extended release (XR) 150-600 mg; desvenlafaxine 50-200 mg; citalopram 20-80 mg; or duloxetine 60-180 mg; buproprion 150-450 mg; mirtazapine 15-45 mg, tricyclics (standard dosing, individually per label instructions).

Phase II (3 weeks) mixed salts amphetamine adjunctive to ADT (as in Phase I).

Interventions: intervention 1: mixed salts amphetamine
Intervention descriptions: intervention 1: adjunctive to ADT

Protocol document:
Prot_SAP_000.pdf: 
Protocol, including statistical analysis plan 
Title:  A randomized, double-blind, placebo-controlled, parallel-group study of adjunctive mixed 
salts amphetamine in adult outpatients with major depressive disorder responding inadequately 
to current antidepressant therapy 
NCT #: NCT02058693
Document version date:  29Nov2010 
Document most recent IRB approval date 25Sep2013


 
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A randomized, double-blind, placebo-controlled, parallel-group study  
of adjunctive mixed salts amphetamine in adult outpatients with major depressive disorder  
responding inadequately to current antidepressant therapy 
 
Corey Goldstein, MD, John Zajecka, MD, Michael Topel, MA, Patricia Meaden, PhD,  
Jagannath Devulapally, MD & Ian Mackey, PA-C 
Department of Psychiatry 
Rush University Medical Center 
1700 West Van Buren Street, Fifth Floor 
Chicago, Illinois 
 
Phone: 312-942-5592 
Fax: 312-942-2177 
 
 
 


 
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PROTOCOL 
 
Title of Study: A randomized, double-blind, placebo-controlled, parallel-group study of flexible 
dose mixed salts amphetamine (5-60 mg) adjunctive to antidepressant therapy among 
adult outpatients with major depressive disorder responding inadequately to current 
antidepressant therapy 
 
Authors:   Corey Goldstein, MD, John Zajecka, MD, Michael Topel, MA, Patricia Meaden, 
PhD, Jagannath Devulapally, MD & Ian Mackey, PA-C 
 
University/Hospital Setting for Conduct of Research: Rush University Medical Center, 
Department of Psychiatry, Chicago, Illinois; and satellite site in Skokie, Illinois 
 
Study Phase:  4  
 
Introduction/Background: 
Significance 
Despite an array of treatment options, major depression continues to be a prevalent, debilitating 
illness. An estimated 13 to 14 million American adults experience debilitating depression; it is a 
more common than asthma, diabetes or angina.  In fact, depression is one of the most frequently 
encountered presentations by primary care physicians (Berman, 2009).  Two-thirds of patients 
who are new to antidepressant medications do not report a timely remission of symptoms, as 
conventionally defined by a minimally 50% reduction in symptom severity and achievement of 
an absolute measured score below a specified cut-off level (Fava, 2003; Fava & Davidson, 
1996); forty to fifty percent of patients receiving new AD medication fail to experience a 
response that is timely.  The statistic that 10 to 20% of care-seeking depressed patients remain 
significantly symptomatic after 2 years exacerbates these figures (Scott, 1988).  Only about one-
third of treated patients experience, whether on mono- or adjunctive-therapy, robust remission of 
symptoms, and this low rate despite the appearance of a number of new treatments for depression 
in the last few years (Berman, 2009).  The cost to society of so many incompletely remitted 
patients is high: a study as long ago as 1990 stated the then-current cost of depression in the US 
as $44 billion annually.  And this figure was exclusive of significant out-of-pocket costs to 
families, estimated then to be $5,000 per worker, per year (Davidson & Meltzer-Brody, 1999).  
The current cost of unsuccessfully treated depression is estimated at 83 billion dollars annually 
(Fleurence, 2009).  The cost to families and loved ones, and the cost of lost opportunity and life 
experience for depressed individuals personally is incalculable. 
 
Treatment Refractory Depression 
While there may be a lack of consensus in precisely defining criteria for an “incomplete 
response” to antidepressant therapy (ADT) (e.g., “treatment refractory,” “treatment-resistant,” 
“non-responders,” “difficult to treat,” or “incomplete responders”), it is widely recognized that 
many patients do not achieve a complete response (remission), and up to 10% of all depressed 
patients receiving treatment fail treatment completely (Goren, 2001).  “Treatment resistance,” for 
our purpose, is defined as the failure of at least one adequate trial of an antidepressant 
medication (Carvahlo, Machado & Cavalcante, 2008).  We note that the associated public health 
burden referenced above is derived from all patients with continued symptoms, and this includes 


 
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those conventionally termed “responders” yet who have not achieved a true remission.  
Importantly, residual symptoms are associated with an increased risk of relapse (Londen, 1998; 
Thase, 1992), impaired social and occupational functioning (Judd, 1998; Paykel, 1995; Miller, 
1998), and, obviously, chronicity (Judd, 2000). Based on these findings, achieving sustained 
remission is the commonly accepted “gold-standard” of therapeutic goals (Zajecka, 2003; Thase, 
2003).  
 
Again, in spite of the continuing swell in both the number and diversity of pharmaceutical 
medications with antidepressant mechanisms (Papakostas and Fava, 2005), accumulating data 
indicates that many patients suffering from major depression have persistent symptoms in spite 
of treatment efforts.  To wit, Corey-Lisle et al (2004) reported that “approximately 22% of 
patients receiving treatment for depression by their primary-care physicians remitted following 6 
months of treatment.”  Similarly, Rush et al (2004) reported only an “11% remission rate among 
depressed outpatients” following 12 months of ADT in “one of several public-sector community 
clinics.”  In the course of the Sequenced Treatment Alternatives to Relieve Depression 
(STAR*D) study, Trivedi et al. (2006) followed nearly 3,000 outpatients with MDD who had 
been prescribed open-label citalopram.  The authors reported remission rates of 28-33%.  Finally, 
Petersen et al (2005) studied outpatients with MDD enrolled in “one of two hospital-based, 
academically-affiliated depression specialty clinics (namely, Massachusetts General Hospital, an 
affiliate of Harvard Medical School and Rhode Island Hospital, an affiliate of Brown 
University),” and reported a 20.5-30.7% remission rate among patients receiving a single 
treatment.  To complicate matters further, even among patients achieving remission residual 
symptoms are common (Nierenberg et al, 1999). These lingering symptoms are associated with 
reduced adaptive psychosocial functioning (Papakostas et al, 2004a), as well as increased 
(Paykel et al, 1995) or accelerated (Judd, 1998, 2000) relapse rates.  In addition to this burden to 
society of incomplete symptom remission or relapse, the side-effect burden of many ADs is high.  
Common AD and atypical antipsychotic medication side effects include weight gain, metabolic 
syndrome, extra-pyramidal symptoms, sexual dysfunction and somnolence (ibid), and it is 
axiomatic that high side-effect burden equals low medication compliance. 
 
Augmentation and combination 
Augmentation or combination treatment as a treatment strategy, suggested by some authors as 
preferable to monotherapy as an initial treatment plan is increasingly supported in the literature 
and in clinical practice.  These treatment strategies may increase symptom relief, treatment 
compliance, and ease side-effect burden (Fava & Rush, 2006).  Potential alternative medication 
strategies in difficult cases include the use of lithium, tricyclic medications, buspirone, 
combining medications and switching (Fleurence, 2009).  STAR*D has shown that augmenting 
early, rather than waiting for treatment failure, increases the likelihood of remission and 
decreases the chances of relapse (ibid). 
 
Prompt treatment, especially in the index episode predicts a more robust response.  Conversely, 
delaying augmentation in patients showing resistance to monotherapy has been shown to 
correlate negatively with complete remission and positively with increased chance of relapse, 
even if complete remission is achieved (Rush, 2007).   There is, however, a lack of consensus 
among psychiatrists as to what comprises proper, evidence-based treatment for patients with 
incomplete response, and this is due largely to insufficient data from rigorous studies.  Due to the 


 
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challenge MDD poses to both clinicians and the patients they treat, and, due to the cost to society 
itself, creating new, effective treatment strategies for MDD is needed urgently to further elevate 
the standard of care for depression (Montgomery, 2006).   
 
Switching medications has been shown to be effective treatment strategy in refractory 
depression, as is augmentation, although, obviously, the quality of patient response to the 
selected initial medication tends to predict which of the two second-line treatment approaches 
will be more effective.  That said, generally, patients who initially show an incomplete response 
have shown better improvement with augmentation than that seen with switching (Rush, 2007). 
 
Augmentation Options 
The FDA has approved only 2 medications and 1 medicinal food for adjunctive use with ADs in 
patients failing to show adequate response to AD monotherapy: quetiapine, aripiprazole and L-
methylfolate (ibid).  This governmental approval is consistent with the findings of the STAR*D 
study.  Significantly, STAR*D references for augmentation, however, did not include 
antipsychotics, supplements, or stimulant medications.  Primarily, data that does exist for 
stimulant use in treatment of depression supports it as an augmentation rather than as 
monotherapy (Chiarello & Cole, 1987).  (Note: Symbyax, a combination of fluoxetine and 
olanzapine, has very recently received approval for treatment resistant depression.) 
 
Of these additional approved medications, aripiprazole has been found to be effective in 
increasing interest and motivation as well as enthusiasm.  Aripiprazole does, however, carry a 
side-effect burden.  In a recent acute study of aripiprazole, 18% of subjects experienced 
akathisia; other common side-effects included headache, somnolence, dizziness, restlessness, 
insomnia, constipation, diarrhea, nausea, fatigue, blurred vision and upper respiratory infection 
(Berman, 2009). 
 
The alternative FDA-approved, pharmaceutical, AD-augmenting agent, quetiapine, has been 
shown to improve depressive symptoms, especially insomnia and anxiety. It does, however, also 
carry a side-effect burden.  Garakani, et al. (2009) found weight change, symptoms of dizziness, 
and GI symptoms, the last-mentioned being the only side effect to achieve differentiation from 
placebo.  In extended release quetiapine, McIntyre et al. (2009) found sedation, somnolence, 
EPS, weight gain, and an increase in fasting glucose.   
 
Dopamine and stimulant use in depression 
Common AD medications have focused on 5-hydroxytryptamine (5HT) or norepinephrine (NE) 
although dopamine (DA) is a key endogenous neurotransmitter implicated in regulating mood, 
motivation, one’s level of interest or pleasure, and other key hallmarks of depression (Dunlop & 
Nemeroff, 2007).  The few randomized controlled trials of stimulants’ efficacy available consist 
largely of acute, uncontrolled data (Orr & Taylor, 2007).  There are limited reports in the 
literature of TCA monotherapy failure being rectified by stimulant augmentation (Wharton, 
1991). 
 
A familiar potentiation strategy is that of TCAs via methylphenidate (MPH).  Gwitzman (1994) 
found that MPH speeds the effect of TCA response, especially in the first and second weeks of 
treatment.  Studies of stimulant augmentation of ADT have been conducted, but with mixed 


 
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results.  Fawcett, et al (1991) found clinically significant results with TRD patients when 
combining pemoline or dextroamphetamine with MAOIs.  SSRIs in combination with MPH or 
dextroamphetamine have been commonly utilized clinically (Shelton, 2010).  Candy et al (2009) 
reviewed 24 randomized, controlled trials of five psychostimulants using as monotherapy for 
depression, and found that only 13 of the 24 had “some useable data,” and among these, only 
three demonstrated “oral psychostimulants significantly reduced short-term depressive symptoms 
in comparison with placebo.”  These authors characterized the quality of the reviewed studies as 
generally “low.”  Conversely, Fawcett, et al. (1991) found that a majority (78%) of study patients 
had a good response to at least one stimulant plus a monoamine oxidase inhibitor (MAO-I).  
Significantly, the authors of this study documented the safety of adjunctive stimulant medication 
in this population.   
 
Similarly, treatment-resistant depression subjects unresponsive to MAOI monotherapy or to 
MAOI administered with a TCA did respond upon the addition of amphetamine or 
methylphenidate (Feighner, et al., 1985).  It is interesting to note that of the five reviewed 
stimulants, pemoline is no longer available, and modafinil is not, strictly speaking, a 
psychostimulant, but rather, may elevate the release of norepinephrine and dopamine from 
synaptic terminals and elevate hypothalamic histamine levels (Ishizuka, Murakami & 
Yamatodani, 2008). 
 
There is little research evidence supporting the use of stimulants as augmenting ADs.  As of 
2007, no randomized controlled trials (RCTs) of stimulant augmentation for TRD existed 
(Carvahlo, 2007).  Stimulant monotherapies currently studied include methylphenidate, 
methamphetamine, dexamphetamine, pemoline and modafinil (Candy 2009).  These studies have 
shown positive findings for improvement in anergia and fatigue symptoms, with only slight 
improvement in mood.  General mood symptoms as measured by the MADRS did not typically 
differentiate from placebo. Cited concerns included the short half-life of stimulant medication 
and the risk of abuse of the medication (Carvahlo, 2008).   
 
MPH has been found to successfully augment citalopram in elderly patients; 8 of 10 patients so 
treated showed clinically significant improvement by week 8 (Lavretsky & Kumar, 2001).  In a 
subsequent pilot study, Lavretsky et al. found that 5 of 6 patients randomized to active 
citalopram and MPH achieved remission (HDRS-24 ≤ 10) compared with none of those in the 
CIT plus placebo group (2006).  Concordantly, Masand et al. (1998) found in their 7-case series 
that every patient, previously responding only partially to a 2nd generation AD, achieved a 
marked improvement, especially in apathy and fatigue, when augmented with a stimulant.  
Consistent with these findings, Fleurence, et al. (2009) found in their review of TRD 
augmentation studies that Hamilton and Montgomery-Asperg symptoms do not generally 
improve with stimulant augmentation, however, CGI scores do improve, as do measures of sleep 
and energy.  Wagner et al (1997) found that 95% of studied patients (male, HIV positive) who 
completed at least six weeks of treatment reported substantial improvements with regard to both 
mood and energy at a median dosage of 10 mg per day of dextroamphetamine.  Olin and 
Massand (1996) found that 83% of a group of hospitalized cancer patients achieved some 
improvement of depressive symptoms when treated with either dextroamphetamine or 
methylphenidate; 73% showed marked or moderate improvement.   
 


 
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Stimulant augmentation of ADs’ particular efficacy 
The few rigorous studies of stimulants’ efficacy available consist primarily of acute, 
uncontrolled data (Orr & Taylor, 2007).  There are a small number of findings in the literature of 
TCA monotherapy failure being successfully augmented by stimulant medication (Wharton, 
1991).Gwitzman (1994) found that, especially in the first and second weeks of treatment, MPH 
speeds the effect of TCA response, Fawcett, et al (1991) found clinically significant results with 
TRD patients when combining pemoline or dextroamphetamine with MAOIs. It is a common 
clinical practice to use SSRIs in combination with MPH or dextroamphetamine (Shelton, 2010). 
 
In elderly patients, methylphenidate has been found to successfully augment citalopram; 8 of 10 
patients so treated showed clinically significant improvement, although improvement did not 
necessarily occur previous to week 8 (Lavretsky & Kumar, 2001).found that 5 of 6 patients 
randomized to active citalopram and MPH achieved remission of symptoms (HAM-24 ≤ 10) 
compared with none of those randomized to the CIT plus placebo group so remitting (2006).  
Concordantly, Masand et al (1998) found in their 7-case series that every patient (previously 
responding only partially to a 2nd generation AD) achieved a marked improvement, and we note, 
especially in the symptoms of apathy and fatigue, when augmented with a stimulant.(2009) 
found in their review of TRD augmentation studies that symptoms rated by the Hamilton and 
MADRS scales do not generally improve with stimulant augmentation, however, CGI scores do 
improve, as do measures of sleep and energy.   
 
Selegiline, an MAO inhibitor, through certain of its metabolites (L-amphetamine and L-
methamphetamine) is known to increase DA synthesis.  Feinberg (2004) reviews the efficacy of 
augmentation of MAOI ADs with selegiline and proposes the practice may have some clinical 
utility, including in cases of TRD.  The author notes that the availability of transdermal selegiline 
would decrease the potential for abuse of add-on stimulant medication.  Again, further study is 
recommended by the author. 
 
Ng’s 2009 report of his survey of New Zealand psychogeriatricians finds that stimulants are 
consistently and successfully, if not frequently utilized in that population to augment treatment-
resistant cases.  He later elaborated (2009) that such stimulant augmentation improved 
specifically fatigue and apathy, promoting wakefulness, alertness, and possible mood 
enhancement.  In a further elaboration, Ng (2009) explores whether psychostimulant medication 
may have efficacy among treatment-resistant cases across a broader demographic.  The above 
findings are consistent with this study’s assertion that depression is usefully conceptualized as a 
disorder comprised of a constellation of symptom domains, each domain potentially responding 
best to a particular treatment strategy. 
 
Larger, higher quality trials are commonly recommended by authors writing on this matter, and 
stimulant medication is suggested as deserving of serious consideration as a treatment 
alternative, despite the limited supporting evidence gathered to date (Orr & Taylor, 2007; Parker 
& Brotchie, 2009).  The literature evaluating research on the use of stimulant medications as 
monotherapy or for adjunctive use have consistently cited the need for larger, randomized-
controlled studies of this treatment modality (Candy, 2009; Dunlop & Nemeroff, 2007; Davidson 
& Meltzer-Brody, 1999; Carvahlo, 2008). 
 


 
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Questions about both the difficulties encountered with patient medication compliance and abuse 
of stimulants have been raised (Orr & Taylor, 2007).  Misuse of stimulant medication is a 
commonly held concern by prescribing clinicians.  Psychostimulant medications “possess 
significant abuse potential because of their ability to stimulate brain reward system pathways 
such as [the] mesocorticolimbic dopamine [pathway]…” (Tremblay, 2002).  Lessenger and 
Feinberg (2007) found that, in 2005, prescribed and OTC medications were intentionally 
misused or used for non-medical purposes by 6.4 million persons 12 years and older during the 
past month.  Of the medication classes examined for abuse, 1.1 million had misused stimulant 
medications.  Among adults 18-25, the monthly misuse of prescription drugs increased from 
5.4% to 6.3%.  The authors describe stimulant medications as being of “particular concern:” in 
2004, there were 7873 American visits to the ER due to non-medical use of stimulant 
medications. 
 
Masand, et al, (1998) found no evidence in their case series of drug-seeking, tolerance or 
dependency among their patients augmented with stimulant medication.  Further, our group has 
over 25 years of experience in the use of stimulant medications for affective disorders; we have 
not seen any evidence for an increased risk of abuse potential.   
 
Chronically depressed individuals may, additionally, show a compensatory up-regulation of D2 
receptors.  This up-regulation complicates initial administration of stimulant medication as it 
may account for the “high” some patients experience with stimulants (Dunlop & Nemeroff, 
2007).  As depressive physiopathology eases through the initial course of treatment, this up-
regulation normalizes. 
 
Mechanism of Action 
Based on animal studies and other research methods, possible mechanisms of the 
pathophysiology of depression include reward deficits thought to be caused by deficiencies or 
dysfunction in DA regulated CNS systems.  If the reward threshold is too high, the patient may 
experience anhedonia, decreased motivation, impaired concentration (Dunlop & Nemeroff, 2007; 
Cryan, 2003).  Diminished DA effect may be caused by impaired presynaptic release, altered 
intracellular processing, or by a change in the number of post-synaptic receptors.  Dopamine 
operates in the mesocortical (concentration and working memory), mesolimbic (motivation, 
pleasure, reward), nigrostriatal (motor planning), tuberoinfundibular (sexual behavior), and 
thalamic regions of the brain.  Impairment in these systems may especially manifest as a 
decreased ability to work for reward and increase in learned helplessness (Dunlop & Nemeroff, 
2007).  
 
The pathophysiology of MDD consists of “functional changes in the neurotransmitter and 
neuroendocrine systems, such as the monoamines and the hypothalamic-pituitary-adrenal axis, as 
well as functional neuroanatomical changes in the cingulate, insula, amygdala, basal ganglia, 
caudate, and frontal, prefrontal, parietal, and temporal lobes” Tremblay (2002).  The author 
noted a marked positive correlation between depression severity and “degree of 
dextroamphetamine [reward] effects.”  “Patients who were more depressed (Hamilton equals 
greater than 23) experience a greater degree of rewarding effects, whereas patients with moderate 
depression did not differentiate from controls (Tremblay, 2002). 
 


 
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It is commonly held that stimulant medications (eg, amphetamine, methylphenidate, pemoline) 
have mood-elevating effects.  Amphetamine, for example, is primarily an indirect-action 
sympathomimetic agent with certain direct agonist properties, which are achieved through direct 
neuronal release of DA and NE; blockade of catecholamine reuptake and weak monoamine 
oxidase inhibition (Biel & Bopp, 1978).  Alternatively, methylphenidate is similar, structurally 
and mechanistically to amphetamine and pemoline is hypothesized to augment catecholamine 
transmission (Chiarello & Cole, 1987).  AMPH designates an a-methyl-phenmethyl-amine motif.  
“J.H. Biel and B.A. Bopp (1978) state the definitive structural features of AMPH as (1) an 
unsubstituted phenyl ring, (2) a two-carbon side chain between the phenyl ring and nitrogen, (3) 
an a-methyl group, and (4) a primary amino group” (Sulzer, 2005).   
 
Amphetamine refers to the class of drugs that predominantly releases catecholamines by a non-
exocytic mechanism.  Amphetamines elevate extra-cellular levels of catecholamines and 
serotonin.  Amphetamines have been utilized by humans via plant availability in the genus 
Ephedra and the tree Catha Edulis.  B-phenethylamine, phenylethanolamine, tyrosine, and 
tryptamine are formed in the peripheral nervous systems and the brain.  These aromatic amino 
acid metabolites may modulate behaviors such as excitement and alertness (Sulzer et al, 2005). 
 
There is evidence for multiple sites of action by endogenous and synthetic amphetamines.  
AMPH has also been suggested to induce CNS dopamine release.  AMPH is supposed to act on 
membrane transporters and so to aid in dopamine synthesis, and modulate monoamine 
availability in both the cytosol and in synaptic vesicles. and the cytosol, and also to aid in 
dopamine synthesis.  The effect of AMPH on vesicles is unclear.  Stimulants generally create 
dopamine release in the striatum (Sutzer, 2005).  Dopamine is thought to play a role in the 
pathophysiology of depression, either through diminished presynaptic DA release, or through 
changes in number or function of post-synaptic receptors (Dunlop & Nemeroff, 2007).  
Amphetamines act as monoamine oxidase inhibitors and have “effects on plasma membrane and 
vesicular transporters to increase the quantity of biogenic amines available for release by 
inhibiting [monoamine oxidase]” (Sulzer et al 2005). 
 
Defects in the underlying “brain reward system may underlie specific and core symptoms of 
depression such as loss of pleasure or interest.”  The brain reward system consists of “extensive 
pathways that mediate behavioral components of reward such as pleasure and motivation.”  
Brain reward system studies in humans have pointed to this circuit’s involvement in the reward-
activities of psychoactive compounds such as of cocaine, nicotine and dextroamphetamine 
(Tremblay, 2002). 
 
“AMPH has long been noted to enhance dopamine synthesis, and this provides an important role 
in its action under some conditions.”  (Sulzer et al 2005).  Wharton (1991) found 
methylphenidate “appears to involve an increase in the blood levels of antidepressants through 
enzymatic inhibition of the metabolism of imipramine,” as does methyl imipramine, which 
increase is concomitant with clinical improvement. 
 
According to David Mrazek (2010), dopamine transport is modulated by the SLC6A3 gene, the 
dopamine transporter gene, known as DAT or DAT1.  This gene “produces a protein that transfer 
dopamine from the synapse back to the neuron” (p. 125).  This is important because reuptake of 


 
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DA back into the neuron switches off DA stimulation in the synapse.  Variations in this gene 
may be implicated in disorders such as “ADHD, binge eating, depression, bipolar disorder, and 
alcoholism (Mrazek, 2010, p. 125). 
 
Mrazek also addresses the DRD4 DA receptor gene and the D4 DA receptor.  This receptor is 
“located predominantly in the prefrontal cortex” (p. 207).  Variations in the density of D4 
receptor in the PFC have been implicated in diseases such as Parkinson’s and schizophrenia.  
Mutations in the DRD4 gene have also been implicated in ADHD (2010).  For all the limitations 
in study methodology and other design factors determining study significance, sufficient 
evidence clearly exists, both clinically and scientifically, supporting the need for further inquiry 
into to the use of DA modulating (stimulant) medications in mood disorders; specifically, in 
treatment-resistant depression. 
 
Primary Objective: Generate evidence-based data on the efficacy, safety and tolerability of 
flexible dose mixed salts amphetamine (MSA) adjunctive to antidepressant therapy (ADT) 
among adult outpatients with major depressive disorder (MDD) who have responded 
inadequately to at least 8 weeks of ADT. 
 
Research Hypotheses: 
1. Primary outcome: The group treated with MSA adjunctive to ADT will show a greater 
mean change from baseline to endpoint in total score as compared to the group treated 
with placebo (PBO) adjunctive to ADT as measured by the 
a. Massachusetts General Hospital Cognitive-Physical Function Questionnaire 
(MGH-CPFQ) 
 
2. Secondary outcome:  
a. MSA adjunctive to ADT will demonstrate clinically acceptable safety and 
tolerability, compared to placebo, based on 
i. spontaneously reported adverse events and significant adverse events 
 
ii. significant changes in blood pressure and pulse 
iii. significant changes in weight 
iv. significant changes in electrocardiogram 
v. significant changes in the Rush Sexual Inventory 
 
b. The group treated with MSA adjunctive to ADT will show a greater mean change 
from baseline to endpoint as compared to the group treated with PBO adjunctive 
to ADT as measured by the change on 
i. MGH-CPFQ individual item analysis 
ii. MADRS scores: 
1. Total score 
2. Subscales 
3. Individual item analysis 
4. Percent of "responders" (≥ 50% reduction in score baseline to 
endpoint) 
5. Percent reaching "remission" (score of ≤ 10 at endpoint) 
 


 
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c. The group treated with MSA adjunctive to ADT will show statistically significant 
improvement in core residual symptoms of MDD extant on monotherapy ADT as 
measured by the  
i. PGI (Patient Impression and Improvement) scales 
ii. Quick Inventory of Depressive Symptomatology-16 (QIDS-16) total score 
(≤ 6) and subscale 
iii. Clinical Global Impression-Severity (CGI-S); and, Clinical Global 
Impression-Improvement (CGI-I) 
iv. QIDS total score and subscale 
 
d. The group treated with MSA adjunctive to ADT will show statistically 
significantly improvement in overall functioning (work, social and cognitive) 
when compared to the group treated with PBO and ADT as measured by the  
i. Total and individual item scores from the HDRS-17 and -28 
ii. Maier and other subscale scores from the HDRS-17 and -28 
iii. Scale For Assessment Of Negative Symptoms (SANS) 
iv. Health Status Questionnaire, 2nd ed. (HSQ 2.0) 
v. SF-36 Health Survey (SF36) 
vi. Fawcett Experienced Pleasure Index (EPI) 
vii. Endicott Work Productivity Scale (EWPS) 
viii. Sheehan Disability Scale (SDS) 
ix. Fatigue Associated with Symptoms of Depression (FASD) 
 
Study Design:  A randomized, double-blind, placebo-controlled, parallel-group study of flexible 
dose mixed salts amphetamine (5-60 mg) adjunctive to antidepressant therapy among 
adult outpatients with major depressive disorder responding inadequately to current 
antidepressant therapy. 
 
Fig. 1: Treatment Groups 
  
Group 1 Group 2 
Phase 1 
PBO 
MSA 
Phase 2 
MSA 
MSA 
 
 
 


 
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Fig. 2: Study Design Overview 
Visit  
Phase 
Weeks 
 on med 
Group 
1 
Group 
2 
Procedures 
V1 
 
Scr 
 
 
Inclusion/Exclusion 
V2 
 
0 
 
 
Baseline measurement + disp. 
 
 
 
 
 
 
V3 
I 
1 
MSA 
PBO 
Measure effect of 1 week on study med + disp. 
V4 
I 
2 
MSA 
PBO 
Measure effect of 2 weeks on study med + disp. 
V5 
I 
3 
MSA 
PBO 
Measure effect of 3 weeks on study med + disp. 
 
 
 
 
 
 
V6 
II 
4 
MSA 
MSA 
Measure effect of 3 weeks on study med + disp. 
V7 
II 
5 
MSA 
MSA 
Measure effect of 3 weeks on study med + disp. 
V8 
II 
6 
MSA 
MSA 
Measure effect of 3 weeks on study med 
 
 
 
 
 
 
V9 
 
(8) 
 
 
Safety follow-up 
 
The treatment phase of the study consists of 2 phases (21 treatment days per phase).  Study Phase 
1 will consist of visits 2 (baseline) through 5.  Study Phase 2 will consist of visits 6 through 8.  
There will be a follow-up visit 2 weeks following visit 8.  There is a one-week interval between 
study visits, with a scheduling window of +/- 3 days allowed. 
 
Mixed salts amphetamine is FDA-approved for Attention Deficit-Hyperactivity Disorder 
(ADHD) and superior in efficacy to placebo; therefore, comorbid ADHD will be statistically 
controlled as a continuously-variable covariate, but will not be considered an exclusionary 
condition.   
 
The primary analysis will be a repeated measures analysis of variance using a mixed-effects 
model (PROC MIXED-MMRM). The primary outcome measure will be the MGH-CPFQ total 
score at baseline and the MGH-CPFQ total score at the end of the trial.  The independent 
variables will be the study visit, the treatment in the previous phase, and treatment assignment. 
The variance covariance matrix for the repeated measures will be unspecified. 
 
Enrollment Period:  The enrollment period is estimated to be 6 months.  The last patient is 
expected to complete the study by March 31, 2010. 
 
Number of Subjects:  40 subjects will be randomized (20 to each treatment arm).  Additional 
subjects may be consented to allow for screen failures.  Subjects who terminate early post-
randomization will be replaced only sufficiently to ensure a total number of 24 (12 to each 
treatment arm) evaluable subjects. 
 
Duration of Subjects' Study Participation:  There will be a total of 9 study visits over a period 
of 9 weeks. 
 
 
 


 
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Inclusion Criteria: 
1) 
Male or female outpatients between the ages of 18-70. 
2) 
Subject must meet criteria for single or recurrent, non-psychotic episode of MDD 
according to DSM-IV-TR diagnosis, as determined by Structured Clinical Inventory of 
Depressive Symptoms (SCID) and confirmed by assessment of investigator.   
3) 
Current depressive episode must be at least 8 weeks in duration. 
4) 
HDRS-17 score ≥ 14 at both the screen and baseline visits. 
5) 
Subject must have been receiving an adequate, stable dose of ADT, based on 
Massachusetts General Hospital-Antidepressant Treatment Response Questionnaire 
(MGH-ATRQ). 
6) 
Subject must be responding inadequately to his/her current monotherapy ADT in the 
current major depressive episode (MDE). 
7) 
Subjects must be able to read and understand English and be able to provide written 
informed consent. 
8) 
Subjects must be considered reliable, able to comply with protocol requirements and 
understand the risks and benefits, per the investigator's clinical judgment. 
9) 
Female subjects of childbearing potential must agree to use adequate form of birth 
control throughout the course of the study. 
 
Exclusion Criteria: 
1) 
Inadequate response during the current episode to more than 3 adequate trials of an 
ADT, as defined by the MGH-ATRQ. 
2) 
Psychiatric hospitalization within the last 6 months. 
3) 
Presence of cognitive disorder(s), bipolar disorder, Axis II pathology or other condition 
that investigator believes would interfere with participation in the study. 
4) 
Substance use disorder, current (as defined by DSM-IV-TR SCID) or positive results 
on urine drug screen or laboratory blood tests. 
5) 
Risk to self or others. 
6) 
The presence of any medical condition, current or past, stable or unstable, that 
contraindicates the use of antidepressant medication or mixed amphetamine salts 
medication as determined by clinician's judgment. 
7) 
Clinically significant abnormal findings on physical exam, EKG or laboratory tests; 
current unstable, untreated hypertension in the opinion of the investigator; history of 
cerebrovascular accident (CVA) or seizure disorder (other than febrile childhood 
seizure). 
8) 
Allergies and/or adverse drug reactions to MSA. 
9) 
Failure to respond to an adequate trial of MSA adjunctive to ADT in the current 
episode. 
10) Subjects taking narcotics, herbal/homeopathic remedies and/or other substance with 
psychotropic activity, based upon clinical judgment of study investigator. 
11) Pregnant or breastfeeding women. 
 
Study Procedures: Figure 3 shows study procedures to be performed at each visit.  No study 
procedures will be performed until a subject signs the informed consent document.    
 


 
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Page 13 of 21 
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Screen visit (Visit 1):  Medical and psychiatric history will be taken, a physical examination and 
vital signs will be performed and lab tests done.  Lab tests include CBC, CMP, urine drug screen 
and urine pregnancy test for females of childbearing potential.  If a subject has had the required 
lab tests performed within the past 3 months and can produce the results, lab procedures may be 
waived at the screening visit for that patient (except urine pregnancy test).  The HDRS-17 score 
upon screening will be used to determine entry eligibility (see inclusion criteria).  Beyond the 
patient’s verbal report, we will attempt to obtain medical records (e.g., previous clinician or 
pharmacy records) to document adequate dose and duration of previous/current ADT. 
 
 
Study Phase 1 
Baseline visit (Visit 2):  Screened and eligible subjects will return one week after the screening 
visit.  At this visit (provided entry criteria continue to be met) subjects will be randomized in 
double-blind fashion to one of two treatment groups: 
 
o Group 1:  MSA during both phases; or 
o Group 2:  PBO during Phase 1 followed by MSA during phase 2 
 
Study drug will be dispensed to the subject in sufficient quantity to last until the next study visit 
(7 days +/- 3).   
 
Study visits 3-5:  Following the baseline visit, subjects will return at one-week intervals for study 
visits 3-5.  Study procedures to be performed are reflected in Figure 3.  Phase 2 study drug is 
dispensed at study visit 5. 
 
Study visits 6-8:  Subjects will return at one-week intervals for study visits 6-8.  Study 
procedures to be performed are reflected in Figure 3.  At visit 8, all subjects will receive 
instructions for tapering the dose of the MSA to avoid potential difficulties from abrupt 
discontinuation of the study drug.   
 
Study visit 9:  Subjects will return two weeks following visit 8 for a safety follow-up check.  
Procedures to be performed are reflected in Figure 3. 
 
If a subject withdraws or is terminated early from the study, visit 9 procedures will be performed 
at the final study visit. 
 
All concomitant medications taken during the study will be recorded in the case report form, 
along with dosage information and start and stop dates.  Subjects requiring excluded drugs will 
be discontinued from the study.  Medication management and clinical ratings will be performed 
by the study clinicians. 
 
Subjects who complete the trial will be offered referrals to qualified physicians for the purposes 
of continued care.  At the conclusion of Visit 8, study blind will be removed by an unblinded 
study staff member for facilitation of ongoing treatment by patient’s selected follow-up care 
provider.  At Visit 8, study subjects will be provided a one-month prescription for the dose of 
MSA they are currently prescribed in the study to ease transition to their follow-up care 
physician. 


 
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Page 14 of 21 
11/29/10 
 
At the end of the study, subjects will be followed for up to three months while an appointment 
can be secured with their original treatment provider or with one referred by the research center. 
 
Investigational Product(s), Dose and Mode of Administration, Duration of Treatment with 
Investigational Product(s):  Based upon clinical judgment and ascertained between clinician 
and patient, study drug will be dosed as follows: The total daily dosage of study drug will be 5-
60 mg, supplied in 5 and 10 mg tablets of MSA or matching PBO.   
 
Total daily dosing of the concurrent ADT will be as follows: escitalopram 10-40 mg; fluoxetine 
20-80 mg;  paroxetine CR 25-100 mg (paroxetine 20-80 mg may be substituted if paroxetine CR 
is not available); sertraline 100-400 mg; venlafaxine XR 150-600 mg; desvenlafaxine 50-200mg; 
citalopram 20-80 mg; or duloxetine 60-180 mg; bupropion 150-450 mg; mirtazapine 15-45 mg, 
tricyclics (standard dosing, individually per label instructions). 
 
The dose of MSA begins at 5mg BID.  MSA dose range will be 5mg-20mg BID or TID, not to 
exceed 60mg per day in addition to the stable dose of ongoing ADT.  Each study medication 
tablet will be 5 or 10 mg of MSA or PBO.  Upward titration will be based upon physician’s 
clinical judgment and confirmed by patient’s consent.  
 
 
Subjects unable to tolerate the study medications will be withdrawn from the study. Every effort 
will be made to encourage patients to comply with this dosage regimen and to take all study 
medications and their ongoing concomitant ADT as instructed. All patients will be instructed to 
return any excess medication at each visit. A pill count will be done to corroborate the study drug 
record. Protocol violation will be defined as less than 80% compliance by pill count. 
 
MSA doses will be custom-tapered per physician’s discretion starting at visit 8. 
 
The study medication packager will use a block randomization scheme to distribute the kits 
within each box/block.   
 
Risk/Safety Information:  The principal investigator and subinvestigators are responsible for 
monitoring the safety of the subjects who have entered this study and for alerting the IRB of any 
event that meets IRB reporting criteria.  The investigator is also responsible to follow, through an 
appropriate health care option, adverse events that are serious or that caused the subject to 
discontinue before completing the study.  The subject should be followed until the event resolves 
or is explained.  Frequency of follow-up is left to the discretion of the investigator.   
 
Monitoring and Reporting of Adverse Events and Serious Adverse Events: 
 
Adverse Events: 
All observed or volunteered adverse events, regardless of suspected causal relationship to study 
drug, will be recorded on the case report form and reported to the IRB if reporting criteria are 
met. 
 
 
 


 
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Serious and/or Unexpected Adverse Events: 
Study site personnel will report to the IRB any serious and/or unexpected adverse event 
following IRB reporting guidelines.  A serious adverse event is any adverse experience that 
results in one of the following outcomes, or is significant for any other reason: 
 
• Death 
• Initial or prolonged inpatient hospitalization 
• A life-threatening experience (that is, immediate risk of dying) 
• Severe or permanent disability 
• Cancer 
• Congenital anomaly 
 
Serious adverse events occurring after a subject is discontinued from the study will not be 
reported unless the investigator feels that the event may have been caused by the study drug or a 
protocol procedure. 
 
Unblinding Procedure 
Unblinding may be performed only by unblinded site personnel, under two conditions: 
• If necessary for treatment of the subject in the event of a medical emergency 
• Upon a subject's completion of the study (visit 8), in order to facilitate continuation of 
care by a non-study clinician 
 
Monitoring of Study/Oversight: 
Study staff will monitor source data and case report forms by regular internal monitoring.  . 
 
IRB Review/Ethical Conduct of Study: 
IRB Review:  Prior to enrolling any subjects, documentation will be obtained that the study 
protocol and informed consent form have been approved by the Rush University Medical Center 
Institutional Review Board.  Any change in the protocol or informed consent form will require 
prior written approval except to prevent injury or risk to a subject. 
 
Regulatory Considerations:  This study will be conducted in accordance with the ethical 
principles stated in the most recent version of the Declaration of Helsinki or the applicable 
guidelines on good clinical practice, whichever represents the greater protection of the 
individual. 
 
Informed Consent:  The informed consent document, in conjunction with verbal discussion of the 
protocol, will be used to explain the study, including the risks and benefits, to the subject in 
simple terms before the subject is entered into the study.  The investigator is responsible to see 
that informed consent is obtained from each subject and to obtain the appropriate signatures and 
dates on the informed consent document prior to the performance of any protocol procedures and 
prior to any changes made to a subject’s medical treatment plan for the purpose of study 
participation.  The original signed consent form will be retained by the investigator. 
 
 
 


 
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Confidentiality: 
All information collected about subjects for the purposes of this study will be treated as 
confidential to the extent allowed by law.  The information obtained while subjects are enrolled 
in this study, including all study-related hospital and office records, will be made available to the 
study doctor, Bristol-Myers Squibb, the Institutional Review Board and other regulatory 
agencies, including the United States Food and Drug Administration (U.S. FDA).   
 
Intended Use of Data: 
The results of this research project may be presented at meetings or in publications, but the 
identity of subjects will not be disclosed in such presentations. 
 
Statistical Analysis:         
Study Assessments and Primary Endpoints: The difference in absolute change in score from 
baseline to endpoint in the MGH-CPFQ between the MSA and the PBO groups is the primary 
endpoint.  Key secondary endpoints will be difference in absolute change from baseline in 
MADRS score between MSA and PBO, difference in remission rates (MADRS < 11) between 
MSA and PBO, the change from baseline in total score at endpoint of MGH-CPFQ item analysis, 
difference in change scores on the CGI-S, CGI-I and QIDS.  Safety outcome measures: adverse 
events, physical examinations, vital signs; blood pressure, orthostatic; EKG; Rush Sexual 
Inventory (RSI).   
                 
Statistical Methods:  The randomized sample includes all patients who are randomized.  The 
Safety sample will include those randomized patients who received at least one dose of double-
blind study medication as indicated on the dosing record. The efficacy sample will include those 
patients in the safety sample who have at least one efficacy evaluation post-randomization.  The 
last observation carried forward (LOCF) data set includes data recorded at a given visit after 
randomization, or, if no observation is recorded at that visit, data carried forward from the 
previous postrandomization visit. The LOCF data set is primary, and analysis of the observed 
case data set also will be conducted. 
                 
The primary analysis will compare pooled MGH-CPFQ response rates between PBO and MSA 
and PBO non-responders.  Differences in response rates will be compared using the CMH 
General Association Test.  Descriptive statistics on non-primary groups will be conducted. 
 
This study seeks to estimate the strength of any statistically significant relationship, or effect 
size, in addition to statistical significance of found treatment effects.   
 
Secondary Endpoints Analysis: Differences in remission (defined as an endpoint MADRS score 
<11) rates will be compared using the CMH General Association Test.  Logistic regression 
analysis will be performed to explore the relationship between response and patients’ 
demographics and prognostic variables including baseline QIDS score, gender, site, and age, etc.  
Similar analyses will be performed for remission.   
 
 
 
 
 


 
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Fig. 3:  Study Procedures Table 
 
 
Treatment period 1 
Treatment period 2 
 
Study Visit 
 
V1 
Screen 
 
V2 
Baseline 
 
V3 
 
V4 
 
V5 
 
V6 
 
V7 
 
V8 
 
V9 
F/UP 
End of Week 
-1 
0 
1 
2 
3 
4 
5 
6 
8 
Day 
-7 
0 
7 
14 
21 
28 
35 
42 
56 
Informed consent 
X 
 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
Medical and psychiatric history 
X 
X 
 
 
 
 
 
 
 
SCID 
X 
 
 
 
 
 
 
 
 
Physical exam 
X 
 
 
 
 
 
 
 
 
Vital signs and weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
EKG
 
X 
 
 
 
 
 
 
 
X 
Lab tests*, urine pregnancy test** 
and urine drug screen 
X 
 
 
 
 
 
 
 
X 
MGH-ATRQ 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
Expectation ratings
 
 
X 
 
 
 
 
 
 
 
Clinician-completed surveys: 
 
 
 
 
 
 
 
 
 
     HDRS (17- and 28-item) 
X 
X 
 
 
 
 
 
X 
 
     MADRS 
 
X 
X 
X 
X 
X 
X 
X 
 
     CGI-S 
X 
X 
 
 
 
 
 
 
 
     CGI-I 
 
 
X 
X 
X 
X 
X 
X 
 
     C-SSRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Patient-completed surveys: 
 
 
 
 
 
 
 
 
 
     MGH-CPFQ 
X 
X 
X 
X 
X 
X 
X 
X 
 
     EWPS 
X 
X 
X 
X 
X 
X 
X 
X 
 
     Fawcett EPI 
X 
X 
X 
X 
X 
X 
X 
X 
 
     FASD 
X 
X 
X 
X 
X 
X 
X 
X 
 
     HSQ 2.0 
X 
X 
X 
X 
X 
X 
X 
X 
 
     PGI-S 
X 
X 
 
 
 
 
 
 
 
     PGI-I 
 
 
X 
X 
X 
X 
X 
X 
 
     RSI 
X 
X 
X 
X 
X 
X 
X 
X 
 
     QIDS-16 
X 
X 
X 
X 
X 
X 
X 
X 
 
     SANS 
X 
X 
X 
X 
X 
X 
X 
X 
 
     SDS 
X 
X 
X 
X 
X 
X 
X 
X 
 
     SF-36 
X 
X 
X 
X 
X 
X 
X 
X 
 
Study drug dispensed 
 
X 
X 
X 
X 
X 
X 
X 
 
Study drug accountability 
 
 
X 
X 
X 
X 
X 
X 
X 
Concomitant therapy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
*Including CBC and CMP.  If patient can produce lab results for CBC and CMP performed within the past 3 months, screening 
procedures may be waived. 
**For females of childbearing potential


 
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ICF_001.pdf: 
Consent 
 
Title:  A randomized, double-blind, placebo-controlled, parallel-group study of adjunctive mixed 
salts amphetamine in adult outpatients with major depressive disorder responding inadequately 
to current antidepressant therapy 
 
NCT #: NCT02058693 
 
Document version date:  17Aug2012 
Document most recent IRB approval date:  25Sep2013 
 


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Investigator:
Corey Goldstein, M.D.
Contact Information (address, telephone): 1700 W. Van Buren St., 5
th Floor
Chicago, IL  60612
(312) 942-5592
Title of Study:
A randomized, double-blind, placebo-controlled, parallel-group study of 
flexible dose mixed salts amphetamine (5-60 mg) adjunctive to 
antidepressant therapy among adult outpatients with major depressive 
disorder responding inadequately to current antidepressant therapy
Sponsor: 
        Cheryl T. Herman Foundation
Subject Information Sheet and Consent Document
Introduction
This form provides you with information so you can understand the possible risks and benefits of 
participating in this study; so that you can decide whether or not you want to be a part of this 
research study. Before deciding whether to participate in this study, you should read the 
information provided on this document and ask questions regarding this study. Once the study 
has been explained and you have had all your questions answered to your satisfaction, you will 
be asked to sign this form if you wish to participate.
Why are you invited to participate in this study?
You are being asked to take part in this study because you have major depressive disorder that 
has not responded adequately to prior antidepressant therapy.
Research studies include only people who choose to take part.  Please take your time to make 
your decision and discuss it with your friends, family and/or physician.  Remember that your 
participation is completely voluntary. There is no penalty if you decide not to take part in this 
study or decide later that you want to stop participating in this research study.  Your care at 
Rush University Medical Center will not be affected if you decide not to participate.
What is the purpose of this study?
The purpose of this study is to find out if adding a mixed salts amphetamine (Adderall®), a 
stimulant medication, to current treatment with an antidepressant provides better response than 
remaining on the antidepressant alone.  Mixed salts amphetamine is approved by the U.S. Food 
and Drug Administration (FDA) for the treatment of Attention Deficit Hyperactivity Disorder 
(ADHD), but is not approved for the treatment of depression, as being used in this study, either 
as a single treatment or as a combination treatment.  
How many people are expected to take part in the study?
We expect to enroll 60 subjects in this study at Rush University Medical Center.  This is the only 
ORA: 10101306-IRB01-CR03   Date IRB Approved: 9/25/2013   Expiration Date: 9/25/2014
site participating in this study.


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What will you be asked to do?
If you meet criteria to enter the study, you will come to the research center for a total of 9 study 
visits.  Before we perform any study procedures, you must sign this consent document.  
In order for us to determine if this study is appropriate for you, we will ask you to sign an 
authorization that will allow previous treatment records to be released to us so that we can 
review your treatment history.
Visit 1 - Screen visit
The screen visit is expected to last approximately 2 hours.  Study procedures performed at this 
visit will include: 
Demographic information:  The study doctor or study staff will collect information about 
your date of birth, gender, race, and ethnicity (family background).
Medical and psychiatric history:  The study doctor or study staff will ask about your 
health, and any illnesses or medications you are taking (including over-the-counter 
medications, vitamins, or herbal treatments).  You may have to stop taking some of these 
medications or over-the-counter medications in order to participate in this study.  You 
will also be asked about your emotional and psychiatric history and symptoms and about 
your method of birth control if you are a woman who can have children. 
Physical examination:  You will receive a physical examination, which will include 
assessment of the head, eyes, ears, nose, throat, skin, thyroid, neurological (checking 
things like your reflexes and the reaction of your eyes to light, for example), lungs, heart, 
abdomen (liver and spleen), lymph nodes (feeling for swelling or lumps in areas such as 
your neck and under your arms) and extremities (arms, hands, legs, feet, etc.). Height and 
weight will also be measured and recorded.
Vital signs:  Your blood pressure, heart rate and temperature will be measured and 
recorded.
Blood tests: You will have blood drawn (approximately 1-2 tablespoons) for routine 
blood tests to assess things like your blood sugar and blood minerals (for example, 
sodium and potassium).  If you have had these same lab tests performed within 3 months 
prior to study enrollment and can provide us with a copy of the results, these tests may 
not need to be repeated at this time.
Electrocardiogram (ECG): a test of the heart’s electrical activity.
Urine tests:  You will provide a urine sample (about 1-2 ounces) to test for pregnancy (in 
women of childbearing potential only) and drugs of abuse.  Results of both of these tests 
must be negative for you to participate in the study.  You will be notified if your test 
results are positive.  These results will remain confidential.  
Interviews and Questionnaires: You will be asked questions by the study doctor and 
study staff and asked to fill out questionnaires about your symptoms of depression and 
how your quality of life is affected.  
Visit 2 - Baseline visit
Approximately 1 week following the Screen visit, you will return for a Baseline visit.  This visit 
is expected to last approximately 1 hour.  The study entry criteria will be reviewed to be sure you 
ORA: 10101306-IRB01-CR03   Date IRB Approved: 9/25/2013   Expiration Date: 9/25/2014
still meet the study criteria.  Study procedures will include:


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Medical/psychiatric history and medications:  You will be asked about any changes since 
the last visit.
Side effects and other medications, vitamins or herbal treatments:  You will be asked 
about any problems you have had since the last visit.  You will also be asked if you have 
taken any other medications (including over-the-counter), vitamins or herbal treatments.
Vital signs:  Your blood pressure, weight, heart rate and temperature will be measured 
and recorded.
Interviews and Questionnaires:  You will be asked questions by the study doctor and 
study staff and asked to fill out questionnaires about your symptoms of depression and 
how your quality of life is affected.
Study medication:  The study medication you will receive will be decided by chance (like 
a flip of a coin).  You will have a 3 out of 4 chance of receiving MSA at some point in 
the study and a 1 out of 4 chance of receiving placebo at some point.  This is called a 
double-blind study, meaning neither you nor the study staff will know which treatment 
you are receiving, because all packaging will look the same.  In case of an emergency, 
however, the study staff can find out your assigned treatment if needed.  Placebo is an 
inactive “sugar pill” made to look like the active medication, but it does not have any 
active medication in it. Placebo is used in research studies to help us tell whether the 
medication being tested is effective. 
You will be given a supply of study medication (mixed salts amphetamine or placebo) to 
take until your next study visit along with instructions for how to take the medication 
(quantity to take and how often to take it).  You will be asked to return all unused study 
medication and containers (even if empty) at each visit.
Neither you nor the study staff will know which group you are assigned to.  This is 
known as double-blind.  
Visits 3-5 - Phase 1
After the baseline visit, you will return each week for 6 more study visits.  Each of these visits is 
expected to last approximately 1 hour.  Study procedures will include:
Side effects and other medications, vitamins or herbal treatments:  You will be asked 
about any problems you have had since the last visit.  You will also be asked if you have 
taken any other medications (including over-the-counter), vitamins or herbal treatments.
Vital signs:  Your blood pressure, weight, heart rate and temperature will be measured 
and recorded.
Interviews and Questionnaires:  You will be asked questions by the study doctor and 
study staff and asked to fill out questionnaires about your symptoms of depression and 
how your quality of life is affected.  
Study medication:  At each visit, you will be given a supply of study medication to take 
until your next study visit along with instructions for how to take the medication 
(quantity to take and how often to take it).  You will be asked to return all unused study 
medication and containers (even if empty) at each visit.  
Visits 6-8 - Phase 2
You will return each week for 3 more study visits.  Each of these visits is expected to last 
ORA: 10101306-IRB01-CR03   Date IRB Approved: 9/25/2013   Expiration Date: 9/25/2014
approximately 1 hour.  Study procedures will include:


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Side effects and other medications, vitamins or herbal treatments:  You will be asked 
about any problems you have had since the last visit.  You will also be asked if you have 
taken any other medication (including over-the-counter), vitamins or herbal treatments.
Vital signs:  Your blood pressure, weight, heart rate and temperature will be measured 
and recorded.
Interviews and Questionnaires:  You will be asked questions by the study doctor and 
study staff and asked to fill out questionnaires about your symptoms of depression and 
how your quality of life is affected.  
Study medication:  At each visit, you will be given a supply of study medication to take 
until your next study visit along with instructions for how to take the medication 
(quantity to take and how often to take it).  At visit 8, you will receive specific 
instructions for discontinuing the study medication.  You should follow these instructions 
carefully, as it may not be advisable to stop taking the study medication abruptly.  You 
will be asked to return all unused study medication and containers (even if empty) at each 
visit.
Visit 9 – 2-week follow-up visit
Approximately 2 weeks following the last study visit, you will return for a 2-week follow-up 
visit.  At this visit, the following procedures will be performed:
Side effects and other medications, vitamins or herbal treatments:  You will be asked 
about any problems you have had since the last visit.  You will also be asked if you have 
taken any other medication (including over-the-counter), vitamins or herbal treatments.
Vital signs:  Your blood pressure, weight, heart rate and temperature will be measured 
and recorded.
Interviews and Questionnaires:  You will be asked questions by the study doctor and 
study staff and asked to fill out questionnaires about your symptoms of depression and 
how your quality of life is affected.  
Study medication:  Any unused study medication and containers (even if empty) will be 
collected.
Electrocardiogram (ECG): a test of the heart’s functioning.
Blood tests: You will have blood drawn (approximately 1-2 tablespoons) for routine 
blood tests to assess things like your blood sugar and blood minerals (for example, 
sodium and potassium).  
Urine tests:  You will provide a urine sample (about 1-2 ounces) to test for pregnancy (in 
women of childbearing potential only) and drugs of abuse.  
“After-Study Care”
If you complete the study, or if it is determined that it is not in your best interests to continue in 
the study at any point following Visit 2, we will attempt to provide adequate treatment for a 
limited time through the research center while you transition to the care of a doctor outside of the 
study.  You will be responsible for the cost of medication or other treatment prescribed during 
this transition period.  Whether you submit these costs to your health insurance company is your 
decision.  We are not able to submit insurance claims.  There will be no charge for the office 
visits during this transition.  This transition period and referral to a doctor outside of the study (if 
needed) will be addressed individually and will occur as quickly as possible in order for you to 
secure follow-up care.  The study doctor and study staff will remain medically available during 
ORA: 10101306-IRB01-CR03   Date IRB Approved: 9/25/2013   Expiration Date: 9/25/2014
the transition.  If your new doctor requires information from your participation in the study, the 


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study staff will provide it upon your authorization to do so.
How long will you be in the study?
If you remain in the study for all of the visits, your participation will last approximately 9 weeks.
You may be removed from this study without your consent for any of the following reasons: the 
study doctor decides that continued participation in the study will be harmful to you, you will 
need a treatment not allowed on the study, your disease becomes worse, you are unable to take 
the treatment as indicated, or the study is canceled.
What are the possible risks of the study?
It is possible that you may experience side effects from the study medication. It is also possible 
that the study medication may have no beneficial effect and as a result you may feel that your 
condition is getting worse.  Inform your study doctor immediately if this occurs, and he/she will 
assess your condition and make changes to your treatment if it is required.
Patients taking mixed salts amphetamine may experience the following side effects:  general 
asthenia (weakness), headache, loss of appetite, diarrhea, dry mouth, nausea, agitation, anxiety, 
dizziness, insomnia (inability to sleep), tachycardia (rapid heartbeat), weight loss and urinary 
tract infection.
Please contact the study doctor if you experience any of these side effects or any other side 
effects during the study. 
Sudden deaths, stroke, and myocardial infarction (heart attack) have been reported in adults 
taking stimulant drugs at usual doses for ADHD.  Although the role of stimulants in these adult 
cases is unknown, adults have a greater likelihood than children of having serious heart 
problems, including serious heart rhythm abnormalities, coronary artery disease and other 
serious heart problems. Adults with such abnormalities should generally not consume stimulant 
drugs.
Stimulant medications can cause a modest increase in average blood pressure and average heart 
rate, and some individuals may have larger increases.  Your blood pressure is checked at every 
visit to monitor for significant changes in heart rate and blood pressure.
Taking stimulants may exacerbate (make worse) behavior problems and thought disorders in 
patients with a pre-existing psychotic disorder.  If you experience any signs or symptoms of 
bipolar illness (such as elevated mood or aggressive behavior), or symptoms of psychotic illness 
(e.g., hallucinations, delusional [thinking things that are not true or real] thinking) you should 
discuss these experiences with your study doctor promptly.
Do not take your study medication other than as directed by your study doctor.  Amphetamines 
have the potential for abuse. Tolerance (needing higher doses to achieve a result), extreme 
psychological dependence, and severe social disability have occurred. There are reports of 
patients who have increased the dosage to levels many times higher than recommended. Abrupt 
cessation (stopping suddenly) following prolonged high dosage administration results in extreme 
fatigue (tiredness) and mental depression.  Signs of taking too much amphetamine may include 
ORA: 10101306-IRB01-CR03   Date IRB Approved: 9/25/2013   Expiration Date: 9/25/2014
severe skin conditions, severe inability to sleep, irritability, hyperactivity, and personality 


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changes. The most severe sign of taking too much is psychosis (described in the paragraph 
above).
Toxic symptoms may occur unexplainably at low doses.  Symptoms may include restlessness, 
tremor (shakiness), hyperreflexia (reduced muscular reflexes), rapid breathing, confusion, 
assaultiveness (hostility), hallucinations (seeing or hearing things that are not real), panic states, 
hyperpyrexia (high fever) and rhabdomyolysis (sometimes fatal disease of the skeletal muscle). 
Cardiovascular effects include arrhythmias (irregular heartbeat), hypertension (high blood 
pressure) or hypotension (low blood pressure) and circulatory collapse. Gastrointestinal 
symptoms include nausea, vomiting, diarrhea, and abdominal cramps. Fatal poisoning is usually 
occurs before convulsions (seizures) and coma.
If you believe you have overdosed on your study medication please call 911, or contact your 
study doctor immediately using the provided 24-hour hotline phone number (312-980-0585).
Other risk information
The risks of taking blood may include pain, discomfort, bleeding, bruising, a small blood clot or 
infection at the site the needle enters the body.  In rare cases, fainting may occur.
You may find it uncomfortable answering questions that are included in the questionnaires.  
Some of these questions may ask about difficulties and symptoms you have experienced and 
difficulties you have dealt with in your life, including thoughts or attempts of suicide.
There may be risk of allergy to the study medication used in this study. Signs of an allergic 
reaction may include redness, itching, swelling or (in rare cases) difficulty with breathing, and 
lightheadedness. Severe allergic reactions may result in death. If you feel that you are 
experiencing a severe allergic reaction, first seek treatment and then call your study doctor at 
312-942-5592 or 312-980-0585 (this number is available 24 hours a day).
All medications have side effects, and with research medications some of these can be 
unexpected. Therefore, other possible side effects may occur in addition to those listed above. 
You will be given any new information that may affect your willingness to start or continue in 
the study.  You will be monitored throughout the study in order to minimize risks.
Only you may take the study medication. The study medication must be kept out of the reach of 
children or persons of limited capacity to read or understand.
Use of alcohol and recreational drugs must be avoided while you are in this study because of 
ORA: 10101306-IRB01-CR03   Date IRB Approved: 9/25/2013   Expiration Date: 9/25/2014
potential interference with the study medication.


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Are there any anticipated pregnancy risks?
Women
The effect of the study medication on an unborn child or nursing infant is unknown.
If you are pregnant or breastfeeding, you cannot take part in this study.  A urine pregnancy test is 
required and will be given before you start taking the study medication and at the Visit 9 study 
visit.  Results of the pregnancy test must be negative for you to participate in the study.  You are 
responsible for using an effective birth control method such as birth control pills, barrier method 
(such as condoms or diaphragms), intrauterine device (IUD), hormone implants or surgical 
sterility while you are taking part in this study.  Once you have completed treatment, you may 
discontinue the use of birth control. If you become pregnant while on the study, you must notify 
the study doctor immediately.
Men
You are responsible for using an effective birth control method, such as the ones listed above. If 
you are a male and your female partner becomes pregnant while you are on the study, you must 
notify your study doctor immediately. Once you have completed treatment, you may discontinue 
the use of birth control.
Are there benefits to taking part in the study?
You may not benefit from participating in this study; however, you may experience relief or 
improvement of your depressive symptoms.  You will have the benefit of the psychiatric 
evaluation prior to entering the study, physical examination, laboratory evaluations and general 
health information from your discussions with the study doctor.
Your participation may provide information about the study treatment that may benefit others in 
the future.
What other options are there?
Instead of participating in this study, you may choose to receive another treatment (including the 
amphetamines) from a doctor outside of this study.  Alternative treatments include 
antidepressants, talk therapy and vagus nerve stimulation.
What about confidentiality of your information?
Records of participation in this research study will be maintained and kept confidential as 
required by law.  Information gathered during your participation in this study will be coded with 
a number.
The United States Food and Drug Administration (FDA) will be able to inspect and copy 
confidential study-related records which identify you by name.  Therefore, absolute 
confidentiality cannot be guaranteed.   The Rush Institutional Review Board (IRB) will have 
access to your files as they pertain to this research study. The IRB is a special committee that 
reviews human research to check that the rules and regulations are followed.  
ORA: 10101306-IRB01-CR03   Date IRB Approved: 9/25/2013   Expiration Date: 9/25/2014
If the results of this study are published or presented at meetings, you will not be identified.


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In order to conduct the study, the study doctor, John Zajecka, M.D., will use and share personal 
health information about you.  This includes information already in your medical record, as well 
as information created or collected during the study.  Examples of the information that may be 
shared include your medical history, physical exam and laboratory test results.  The study doctor 
will use this information about you to complete this research.
Confidentiality and disclosure of your personal information is further described in the attachment 
to this form.  The attachment is entitled HIPAA Authorization to Share Personal Health 
Information in Research (2 pages).
What are the costs of your participation in this study?
There is no charge to you for the study medication, study procedures (such as lab tests required 
for this study) and study clinic visits.  You will continue to be responsible for the cost of the 
antidepressant you were taking when you entered the study.  
Parking in the Rush parking lots will be provided at no cost.  Limited assistance may be available 
for travel to and from the study site for study visits.  Please discuss these arrangements with the 
study staff.
This study is supported by a financial grant from the Cheryl Herman Charitable Trust.  This 
financial support covers a portion of study staff salary, supplies, tests and medication needed 
for the study, and other research related costs.  A portion of this money will go to Rush 
University Medical Center to compensate for other institutional research related costs.
Will you be paid?
You will not be paid for your participation in this study.  
What happens if you experience a research related injury?
If you experience any injury or illness as a direct result of your participation in this research 
study, immediate treatment will be provided. However, the cost of that treatment will be 
billed to you or your insurance company. 
If you have any medical problems during the study, please contact the study doctor, they will 
explain your treatment options to you or tell you where you can get treatment. 
Rush University Medical Center has no program for financial compensation or other 
forms of compensation for injuries which you may incur as a result of participation in this 
study.
What happens if you need emergency care?
If you need emergency care while you are participating in this study, it is important that you 
inform emergency personnel of your participation in this study.
Whom do you call if you have questions or problems?
Questions are encouraged.  If there are any questions about this research study or if you 
experience a research related injury, please contact Dr. Corey Goldstein at 312-942-5592 or 312-
ORA: 10101306-IRB01-CR03   Date IRB Approved: 9/25/2013   Expiration Date: 9/25/2014
980-0585 (outside of usual business hours).  Questions about the rights of research subjects may 


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be addressed to the Rush Research & Clinical Trials Administration Office at 312-942-5498.
By signing below, you are consenting to participate in this research study.  You have read the 
information given or someone has read it to you. You have had the opportunity to ask questions, 
which have been answered satisfactorily to you by the study personnel. You do not waive any of 
your legal rights by signing this consent document. You will be given a copy of the signed and 
dated consent document for your records.
SIGNATURE BY THE SUBJECT:
Name of Subject
Signature of Subject
Date of Signature
SIGNATURE BY THE WITNESS:
I observed the signing of this consent document.
Signature of Witness
Date of Signature
SIGNATURE BY THE INVESTIGATOR/INDIVIDUAL OBTAINING CONSENT:
I attest that all the elements of informed consent described in this document have been discussed 
fully in non-technical terms with the subject.  I further attest that all questions asked by the 
subject were answered to the best of my knowledge.  
Signature of Individual Obtaining Consent
Date of Signature
ORA: 10101306-IRB01-CR03   Date IRB Approved: 9/25/2013   Expiration Date: 9/25/2014
Signature of the Investigator
Date of Signature