Substance Use Disorder Journal Club

Substance Use Disorder Journal Club

Imagine yourself sitting around table drinking morning coffee with your colleagues and talking shop. Reading this journal article review on your own is more than a smidge shy of that but you can do it in your soft pants so maybe it’s a decent trade.

Hope you enjoy,

Andrea Truncali

Atomoxetine and OROS methylphenidate performed similarly in patients with comorbid major depression and ADHD.

Shim SH, et al. Comparison between Atomoxetine and OROS Methylphenidate as an Adjunctive to SSRIs in Attention-deficit/Hyperactivity Disorder Adults with Comorbid Partially Responsive Major Depressive Disorder: A Head-to-head, 12-week, Randomized, Rater-blinded Clinical Trial. Clin Psychopharmacol Neurosci. 2022 Feb 28;20(1):143-153. doi: 10.9758/cpn.2022.20.1.143. PMID: 35078957; PMCID: PMC8813317.


This is a single blind 12week randomized trial comparing atomoxetine vs OROS (osmotic controlled release oral delivery system) methylphenidate in patients with major depression (MDD) and ADHD who had no or partial response to SSRI therapy.

Population: Patients aged 19-65 were recruited from three university hospitals in the Republic of Korea from Jan 2018-Dec 2019.  

Patients were eligible if diagnosed with MDD and ADHD by DSMV and had not responded or partially responded to 8-12wks of escitalopram, sertraline or fluoxetine, defined as a HAM-D >=16 [1]. ADHD dx was confirmed using the Mini-International Neuropsychiatric Interview.[2]

Patients were excluded if they had bipolar disorder, substance use disorders, eating disorders or were suicidal. No exclusions mentioned for PTSD or anxiety. Patients were not permitted any other psychotropic drugs except for benzodiazepines (2mg/day of lorazepam or equivalent).

Design: Prospective, randomized, active-controlled trial.  Allocation to study groups was not detailed. Raters were blinded to the assigned treatment but patients were not. It is unclear if the treating clinicians were also the raters.

Intervention: Patients received 12wks of atomoxetine (ATX) or OROS methylphenidate (MPH) in addition to pre-existing SSRI therapy. Dosing was based on prescribing information and clinical judgement of the clinicians. Visits were not described but patients were assessed at 2, 4, 6, 8 and 12wks.

Follow up period: 12wks of treatment, 12 wks of observation

Outcomes: Primary outcomes were change in the HAM-D and the Korean version of the WHO Adult ADHD self report scale (ASRS)[3].  Four related assessments were also obtained. [4]

Power calculation was not reported.  Management of missing data and those who discontinued treatment was not detailed.



60 patients enrolled and had the following characteristics:  average age 23, 80% male, 76% “drinkers”, 52% “smokers”, avg 12yrs of education, duration of illness 3.5yrs, baseline HAM D ~21, ASRS 42, normal baseline BP and BMI 24. No significant differences between groups except for higher proportion of smokers in the MPH than ATX (66vs 36%) -adjustment made in the analysis for this. Majority (85%) of the patients were taking escitalopram 10-20mg/day; 10% other SSRIs, 5% not reported.

Mean doses of medication achieved in the study were ATX 65mg/day, MPH 57mg/day.[5]

Patient Follow up:

N enrolled
N (% of subgroup) completed
Reasons for withdrawl/loss



41 (68%)



19 (68%)

5 lost to fup, 3 headache, 1 sedation



22 (69%)

4 lost to fup, 2 headache, 2 wt loss, 1 palpitations, 1 tremor

Main outcomes:

Changes over time in scores on HAMD and ASRS for ATX vs MPH.

Depression score (HAMD) over time

Depression score (HAMD) over time

ADHD sx score (ASRS) over time

ADHD sx score (ASRS) over time

ATX (n=28) Mean (SD)
MPH (n=32)
P for difference

HAM D wk 2

-1.9 (2.6)

-1.7 (3.0)


HAM D wk 4

-4.5 (4.3)

-4.7 (4.7)

HAM D wk 8

-5.3 ( 6.1)

-4.1 (5.2)

HAM D wk 12

-6.8 (5.2)

-6.5 (5.0)

ASRS wk 2

-1.5 (8.3)

-1.8 ( 5.5)


ASRS wk 4

-5.6 (10.6)

-6.2 (10.1)

ASRS wk 8

-8.4 (11.4)

-6.2 (11.7)

ASRS wk 12

-9.9 (12.5)

-8.4 (10.9)

There were no significant differences between groups for the additional measures collected (CGI-S, CGI-I, CUDOS and SDS).


In patients with active MDD and ADHD taking SSRIs, there was no difference in symptom change with standard doses of 12wks of atomoxetine versus OROS methylphenidate.


ADHD literature consists largely of industry sponsored studies assessing effect of ADHD medication versus placebo. Stimulant therapy is widely considered to be more effective than non-stimulant therapy but this is based largely on informal comparison of effect sizes across studies, not on head to head trials, and the degree of this superiority is not well quantified. [i] Network meta-analyses, which use statistical methods to formally compare effect sizes across studies, have inconsistently supported stimulants as superior to nonstimulants.[ii] [iii]  The trial reviewed here is one of few head to head comparisons, testing atomoxetine against a long acting formulation of methylphenidate in patients with active major depression treated with SSRIs.

The study showed no difference between these two therapies in terms of effect on ADHD symptom scales. It did show improvement over time in both groups, though without a placebo group, one cannot conclude that that change is a result of the medication – it may be due to the attention given in the q2wk visits or expectation bias.

This result mirrors findings in other small trials but it is important to consider the following limitations:

  1. The study may be underpowered -that is, a difference may have been missed due to small sample size and the loss to follow up.

If you want to consider the gorey details, see what a power calculation on sealed suggests:

Assume we want 80% power to detect a difference (ie, 20% chance of a false negative). Also assume (based on other ADHD trials) a 30% symptom reduction will occur with medication (=12pts on the ASRS in this study). We might consider a 40% symptom reduction (=17, d=5) worth notice. To detect that kind of a difference between treatments you would need 100 people (with 100% fup ).

If we were ok with finding a 47% symptom reduction from one treatment, compared to a 30% reduction in the other, a sample size of 40 would be sufficient. (This sample size was 51 with 68% fup.)

The authors do not describe their power calculation, which is not typical of published work.

  1. We don’t know what happened to the data for those who did not complete the study, and this can affect findings (either missing a relationship, or discovering one that is not there). Understanding how the missing data was dealt with can help us draw more valid conclusions about whether the loss to follow up affected the results. In addition, doing a sensitivity analysis can be helpful – ie, reporting what happens when the missing data are treated in a variety of ways such as with missing data entered as no change, as the worst outcome, and/or using last data point available).
  2. Patients, and maybe their treating clinicians, were not blinded to the treatment received. It is hard to know what the impact of this is given (my) lack of familiarity with this population, but it is curious that the investigators did not blind subjects. Lack of blinding can affect outcomes that are largely subjective – in what way might depend on what this population tends to believe about the two, if pts believed that atx was a better treatment than stimulants they might answer questions about improvement favorably. This would affect even a blinded rater’s assessment, and could overestimate the effect of atx. (and same could be true for MPH).
  3. This is a short term study for a therapy that will be long term.   This study does not provide evidence about potential long term benefits (functional outcomes like employment, relationships) or harms (ie, substance misuse, tolerance, cardiovascular outcomes).
  4. Finally, let’s consider external validity – how we apply these findings to populations other than the one studied. This was a study done in a university setting in Korea, with a different care system and culture. The patients were relatively young, largely male, and carried a diagnosis of MDD on SSRIs. Importantly, people with substance use disorders were excluded (but those termed ‘drinkers’, or prescribed benzodiazepines, were included).  How would these differences likely impact the effect (and safety) of a stimulant versus non stimulant? If one of the therapies is affecting ADHD sxs by treating depression, than those without depression may not reap the same benefits. And, given the high likability of stimulants, people with substance use disorders may have higher risk of misuse in the long term (though that outcome is not assessed in this evaluation). 

It would be valuable to conduct a head to head trial of stimulants versus not stimulants in a larger population without depression, in a double blind fashion and over a longer period, in order to overcome the limitations described.  In the absence of that, this study suggests that MPH may not be superior to ATX in this population. And if it is superior (and we don’t see that because of lack of power), the margin of superiority does not appear to be large. 

[1] Hamilton Depression Scale. Generally, scores of 17+ =moderate to severe; range = 0-52.

[2] Structured psychiatric interview used worldwide, requires about 15min to administer.

[3] WHO ASRS, Korean version = 18questions, 5point scale ranging from 0-72. A validation study showed mean score 25 in controls without ADHD ,and 37 in those with ADHD as confirmed on the MINI.

[4] Additional assessments: Clinical global impression improvements and severity (CGI- I and CGI-S), CUDOS (depression scale), Sheehan Disability Scale (SDS)).

[5] Typical adult dosing 40-100mg atomoxetine; OROS MPH (Concerta) 18–72 mg/day, where 18mg OROS~5mg bid-tid IR MPH , 72mg OROS ~20mg bid-TID

[i] Volkow ND, Swanson JM. Clinical practice: Adult attention deficit-hyperactivity disorder. N Engl J Med. 2013 Nov 14;369(20):1935-44. doi: 10.1056/NEJMcp1212625. PMID: 24224626; PMCID: PMC4827421.

[ii] Elliott J, Johnston A, Husereau D, Kelly SE, Eagles C, Charach A, Hsieh SC, Bai Z, Hossain A, Skidmore B, Tsakonas E, Chojecki D, Mamdani M, Wells GA. Pharmacologic treatment of attention deficit hyperactivity disorder in adults: A systematic review and network meta-analysis. PLoS One. 2020 Oct 21;15(10):e0240584. doi: 10.1371/journal.pone.0240584. PMID: 33085721; PMCID: PMC7577505.

[iii] Cortese S, Adamo N, Del Giovane C, Mohr-Jensen C, Hayes AJ, Carucci S, Atkinson LZ, Tessari L, Banaschewski T, Coghill D, Hollis C, Simonoff E, Zuddas A, Barbui C, Purgato M, Steinhausen HC, Shokraneh F, Xia J, Cipriani A. Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta-analysis. Lancet Psychiatry. 2018 Sep;5(9):727-738. doi: 10.1016/S2215-0366(18)30269-4. Epub 2018 Aug 7. PMID: 30097390; PMCID: PMC6109107.