Adjunctive Methylphenidate ER in Patients With Schizophrenia to Improve Functional and Cognitive Outcomes

Adjunctive Methylphenidate Extended Release in Patients With Schizophrenia: a Single-centre Fixed Dose Cross-over Open-label Trial to Improve Functional and Cognitive Outcomes

Two of the major features of schizophrenia spectrum illness, negative and cognitive symptoms, have been associated with poor functional outcome and burden of illness. Given the proposed role of dopaminergic hypoactivity, augmentation with psychostimulants has been postulated as one of the potential treatment options for negative and/or cognitive symptoms of schizophrenia. The major drawback for use of these agents is a potential risk of relapse or worsening of psychosis through direct or indirect dopamine agonism activity and a great deal of caution has been called for use of stimulants in individuals with psychosis. However, preliminary results of earlier studies indicated improvement of negative and cognitive symptoms with off-label use of adjunctive psychostimulants. The present study aims to assess off-label use of adjunct psychostimulants in patients with schizophrenia in a tertiary mental health centre, focusing on efficacy and safety.

Study Overview

• Status: Completed
• Conditions: Schizophrenia Schizoaffective
• Intervention / Treatment: Drug: Apo-Methylphenidate ER

Detailed Description

This project focuses on assessing efficacy of off-label use of adjunctive methylphenidate ER 36 mg among 24 stable patients with schizophrenia spectrum illness. This is a single centre study at the Royal Ottawa Mental Health Centre, Ottawa, Canada. An open-label fixed dose controlled cross-over trial is planned. Individuals (inpatients and outpatients) with schizophrenia who are stable on antipsychotic medications will be invited to participate in the study. Participants will be randomized into receiving four weeks of methylphenidate extended release (ER) 36 mg or treatment as usual and will switch group assignments for another 4 weeks. The duration of the study is 12 weeks for each participant, including 8 weeks of treatment (4 weeks treatment as usual and 4 weeks treatment as usual + adjunctive methylphenidate ER) and a follow-up visit at 12 weeks (study end point). A number of standardized scales will be used to measure functional capacity, cognition and symptom severity.

• Study Type: Interventional
• Enrollment (Actual): 35
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Ottawa, Ontario, Canada, K1Z 7K4
      • Royal Ottawa Mental Health Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 51 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Adult between the ages of 18-55; we chose an upper age limit of 55 years to exclude patients with potential age-related cognitive impairments which usually occur about a decade earlier in patients with schizophrenia
• Inpatient or outpatient with schizophrenia spectrum illness, on any antipsychotic medication
• Clinically stable for the past 4 weeks
• Able to communicate in English

Exclusion Criteria:

• Have known sensitivity to methylphenidate ER, as documented in the electronic medical record OR, as reported by the patient AND verified by pharmacy
• Have had treatment with ECT in the past 6 months
• Have a history of traumatic brain injury

• Have a contraindication to psychostimulants including:

  1. Uncontrolled hypertension
  2. Significant cardiovascular abnormality including history of cardiac interventions, history of myocardial infarction, unstable arrhythmia, congenital heart disease
  3. Known family history of premature cardiac death (for males <45, females <55)
  4. Known history of glaucoma
• Are currently pregnant or planning to become pregnant- a rapid urine pregnancy test will be done for female participants, and a refusal to take the test or a positive test will exclude the participant
• Have a diagnosis of substance induced psychosis
• Have any of the following diagnoses: neurodevelopmental delay, intellectual disability or neurocognitive disorder (dementia)
• Have a diagnosis of another currently significant and unstable psychiatric condition (i.e. depressive episode, active substance use disorder, etc.)
• Have a history of previous safety concerns directly driven by positive symptoms (e.g history of suicide attempt as directed by auditory hallucinations)
• Have current active suicidality

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Apo-Methylphenidate ER arm; Apo-Methylphenidate ER, 36 mg, oral, once a day, every morning, 4 weeks duration. Methylphenidate ER will be started at 18 mg to test tolerability and will be titrated at day 7 to a dose of 36 mg.	Drug: Apo-Methylphenidate ER; For inpatients, the study medication will be administered by unit nurses, alongside their other medications. For outpatients, the study medication will be dispensed to the participant by the research assistant during their weekly visit. Patients will continue their regular medications as per standard of care.
No Intervention: Treatment as usual arm; Participants in the treatment as usual arm will continue with their current treatment as decided by their treatment team.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Defined as change in functioning	Change in functioning will be measured using the Virtual Reality Functional Capacity Assessment (VRFCAT) tool. The VRCAT is an interactive computerized measure of functional capacity. It presents the user with real life scenarios such as shopping, taking a bus, completing a recipe, etc, and assesses key instrumental activities of daily living in a realistic and interactive virtual environment.	VRFCAT will be implemented at baseline, week 4, 8 and at follow-up at week 12.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Defined as change in cognitive functioning (domains include verbal memory, working memory, motor speed, attention and processing speed, verbal fluency and executive functioning)	Change in cognitive functioning will be measured using the Brief Assessment of Cognition in Schizophrenia (BACS). The BACS is a tool to assess aspects of cognition found to be the most impaired and correlated with outcome in patients with schizophrenia. It consists of six domains: verbal memory, working memory, motor speed, attention and processing speed, verbal fluency and executive functioning.	BACS will be implemented at baseline, week 4, 8 and at follow-up at week 12.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Defined as symptom severity (items include delusions, conceptual disorganization, hallucinations, blunted affect, social withdrawal, lack of spontaneity/flow of conversation)	Symptom severity will be measured using the Positive and Negative Syndrome Scale 6-item (PANSS-6). The PANSS-6 is a 6-item version of the PANSS scale, and includes P1 = delusions, P2 = conceptual disorganization, P3 = hallucinations, N1 = blunted affect, N4 = social withdrawal, N6 = lack of spontaneity/flow of conversation. Items are rated on a 7-point scale from 1(absent) to 7(extreme), with a total range of 6-42, with higher scores indicative of more severe symptoms. The PANSS-6 has been shown to adequately measure severity, remission, and antipsychotic efficacy related to core positive and negative symptoms in clinical trials and its validity and sensitivity have been demonstrated in treatment resistant schizophrenia.	The PANSS-6 will be completed at all time points (baseline, weeks 1-8, and at follow-up at week 12.

Collaborators and Investigators

• Sponsor: The Royal Ottawa Mental Health Centre
• Investigators: Principal Investigator: Naista Zhand, M.D., Royal Ottawa Mental Health Centre

Study record dates

Study Major Dates

• Study Start (Actual): September 9, 2022
• Primary Completion (Actual): August 21, 2024
• Study Completion (Actual): September 18, 2024

Study Registration Dates

• First Submitted: June 7, 2022
• First Submitted That Met QC Criteria: June 7, 2022
• First Posted (Actual): June 10, 2022

Study Record Updates

• Last Update Posted (Estimated): December 12, 2025
• Last Update Submitted That Met QC Criteria: December 4, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Keywords: schizophrenia; functional outcomes; methylphenidate
• Additional Relevant MeSH Terms: Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders; Schizophrenia; Psychotic Disorders; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Dopamine Agents; Dopamine Uptake Inhibitors; Central Nervous System Stimulants; Methylphenidate
• Other Study ID Numbers: 2021025

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No