Neurocognitive deficits in substance use disorder and comorbid ADHD : predictors of pharmacological treatment response

Background: Attention deficit/hyperactivity disorder (ADHD) is common in patients with substance use disorder (SUD). Comorbid SUD+ADHD is associated with a range of severe complications, compared to having only one of these disorders. While it is well established that numerous neurocognitive impairments are associated with both amphetamine use disorder (ampUD) and ADHD individually, it is unknown how these impairments manifest in comorbid ampUD+ADHD. This is important since it may have clinical implications and provide insights into the mechanisms underpinning the observed challenges in treating this patient population.

SUD+ADHD treatment guidelines recommend targeting both disorders. However, utilizing stimulant treatment, the first-choice pharmacotherapy for ADHD, in comorbid patients is not without controversy. Clinicians may be reluctant to prescribe stimulants due to concerns regarding diversion and misuse, which likely leads to practice variation.

Stimulant treatment in patients with illicit stimulant use disorder (stimUD) and comorbid ADHD using robust doses is associated with a reduction in both substance use and ADHD symptoms. However, the effect of these higher than standard doses on objective measures of neurocognitive functions have not been investigated.

Lastly, prospective real-world data on the clinical course of treatment seeking patients with SUD+ADHD is lacking, especially, regarding which factors contribute to treatment allocation and successful treatment outcomes.

Aims:

I: To explore the effect of robust doses of extended-release methylphenidate (MPH) on neurocognitive functioning in patients with amp-UD+ADHD.

II: To investigate how different facets of impulsive behavior are expressed in patients with ampUD+ADHD.

III: To describe treatments provided for comorbid SUD+ADHD in everyday clinical settings, and to explore factors that influence treatment allocation.

IV: To investigate factors that contribute to successful ADHD and SUD treatment outcomes in a real-world clinical setting.

Methods:

Study I: Adult patients with comorbid ampUD+ADHD received single blinded doses of osmotic-controlled release oral delivery system (OROS) methylphenidate (MPH) with a target dose of 180 mg. Additionally, two other groups (ADHD only and healthy controls (HC)) were recruited. For the ADHD only group the target dose was 72 mg OROS-MPH and HCs did not receive any study medication. Participants were assessed repeatedly with a neurocognitive test battery.

Study II: A cross-sectional study design was employed. Three groups (ampUD+ADHD, ADHD only and HC) were assessed on task-related impulsive choice and self-rated impulsive behavior.

Study III and IV: An observational international prospective cohort design was employed. Treatment seeking patients with comorbid SUD+ADHD were recruited in nine countries at ten study sites. Data was collected through patient files, interviews with clinicians and patients at baseline, three months and nine months, respectively. Additionally, data from patient files on treatment allocation was collected at 4 weeks. Clinical and sociodemographic data was collected along with self-rating scales and structured interviews regarding substance use.

Results

Study I: A total of nineteen participants in the ampUD+DHD group were included, out of which eleven completed the study and reached the target dose of 180 mg OROS-MPH. In the ADHD only group, sixteen participants were included and fifteen reached the target dose of 72 mg OROS-MPH and twenty-one HCs completed the study. On the third assessment (corresponding to a target dose of 180mg OROS-MPH), the ampUD+ADHD group presented with a significant improvement in response inhibition, working memory, sustained attention, self-rated ADHD symptoms and reduced craving, compared to baseline. The ampUD+ADHD group presented with more pronounced impairments in response inhibition, working memory and more self-rated ADHD symptoms, compared to ADHD only.

Study II: Twenty-nine participants with ampUD+ADHD, 25 participants with ADHD only and 116 HC completed screening, including self-rating scales. Twenty, 16 and 114 participants completed computerized cognitive tasks in the ampUD+ADHD group, ADHD group and HC group, respectively. ampUD+ADHD reported significantly higher motor, attentional and non-planning impulsiveness, and presented with a significantly higher degree of impulsive choice, compared to both groups. There were no differences in task-related impulsiveness between ADHD only and HC.

Study III: Five-hundred-seventy-eight treatment-seeking patients with SUD+ADHD were recruited. About two thirds received treatment for ADHD (62.8%), with 54.0% receiving pharmacological treatment, 34.0% receiving psychological treatment, and 25.1% receiving combined pharmacological and psychological treatment. Treatment strategies differed substantially across treatment sites. In addition, higher ADHD symptom severity and sobriety at intake were associated with receiving treatment for ADHD.

Study IV: Stimulant treatment was significantly associated with better SUD treatment retention (OR: 2.4, 95% CI: 1.36-4.23), ≥30% reduction in ASRS total score (OR: 2.6, 95% CI: 1.22-6.12), and fewer heavy drinking days (IRR: 0.24, 95% CI: 0.13-0.42) at three months. Psychological ADHD treatment was significantly associated with fewer heavy drinking days at three months (IRR: 0.27, 95% CI: 0.14-0.51). Pharmacological treatments for SUD were not associated with treatment retention, ADHD nor SUD outcomes.

Conclusions:

I: Patients with ampUD+ADHD present with more severe neurocognitive deficits compared to patients with ADHD only. The effect of 180 mg OROS-MPH on cognition in patients with ADHD+AMPH was inconclusive. Future studies should consider recruitment issues and high drop-out rates in this study population.

II: Patients with ampUD+ADHD have overall elevated levels of impulsivity compared to individuals with ADHD only. In addition, ampUD+ADHD is specifically associated with impairments in task-related impulsive choice, which was not found in ADHD only compared to HC. The neurocognitive profile in this specific patient group may represent a need for more systematic screening within healthcare settings to develop effective and targeted treatment for comorbid patients.

III: SUD+ADHD treatment is suboptimal even in specialized health care centers and with substantial variation in clinical praxis. Further research is needed to better understand the barriers to implement treatment guidelines for ADHD+SUD.

IV: The results from study IV suggests that ADHD treatment is associated with better SUD treatment retention, clinically relevant reductions in self-reported ADHD symptoms and significantly fewer heavy drinking days in patients with SUD+ADHD. This highlights the importance of providing ADHD treatment in this population. Future RCT's are warranted, especially on the effect of ADHD treatment in patients with alcohol use disorder (AUD)+ADHD. Such studies should preferably investigate combinations of ADHD treatments and SUD treatments using different doses of stimulants.

List of scientific papers

I. Brynte C, Konstenius M, Khemiri L, Bäcker A, Guterstam J, Levin FR, Jayaram-Lindström N, Franck J. The Effect of Methylphenidate on Cognition in Patients with Comorbid Attention Deficit/Hyperactivity Disorder and Amphetamine Use Disorder: An Exploratory Single-Blinded within-Subject Study. Eur Addict Res. 2024;30(1):1-13. Epub 2023 Nov 29. PMID: 38029734. https://doi.org/10.1159/000535016

II. Brynte C, Khemiri L, Stenström H, Konstenius M, Lindström NJ, Franck J. Impulsive choice in individuals with comorbid amphetamine use disorder and attention deficit-hyperactivity disorder. BMC Psychiatry. 2023 Jul 24;23(1):537. PMID: 37488536; PMCID: PMC10367266. https://doi.org/10.1186/s12888-023-05034-x

III. Brynte C, Schellekens A, Csaba B, Begeman AHB, Crunelle CL, Daigre C, Demetrovics Z, Dom G, Grau-López L, Hernandez M, Icick R, Johnson B, Kapitány-Fövény M, van Kernebeek M, Konstenius M, Levin FR, Luderer M, Matthys F, Moggi F, Ramos-Quiroga JA, Schleussner L, Therribout N, Thomas A, Vorspan F, van den Brink W, Franck J. Treatments and treatment predictors in patients with substance use disorders (SUD) and comorbid attention deficit hyperactivity disorder (ADHD): First results from the International Naturalistic Cohort Study of ADHD and SUD (INCAS). [Manuscript]

IV. Brynte C, Schellekens A, Csaba B, Begeman AHB, Crunelle CL, Daigre C, Demetrovics Z, Dom G, Grau-López L, Hernandez M, Icick R, Johnson B, Kapitány-Fövény M, van Kernebeek M, Konstenius M, Levin FR, Luderer M, Matthys F, Moggi F, Ramos-Quiroga JA, Schleussner L, Therribout N, Thomas A, Vorspan F, van den Brink W, Franck J. Predictors of treatment success in patients with substance use disorder (SUD) and co- morbid attention deficit/hyperactivity disorder (ADHD): Results from the International Naturalistic Cohort Study of ADHD and SUD (INCAS). [Manuscript]