What is the mechanism of action of this treatment?

Common treatments for Schizophrenia Spectrum Disorder primarily target dopamine receptors, with a focus on D2 receptor antagonists, which help reduce positive symptoms like hallucinations and delusions by blocking dopamine activity. However, these treatments often do not address cognitive impairments and negative symptoms. Novel treatments, such as the dopamine 1 partial agonist CVL-562, aim to modulate D1 receptors, which are crucial for cognitive functions and working memory. By targeting D1 receptors, these treatments hold promise for improving cognitive deficits and overall functional outcomes in patients, addressing a significant unmet need in schizophrenia care.

What side effects are associated with this type of intervention?

Common treatments for Schizophrenia Spectrum Disorder, particularly second-generation antipsychotics, often include side effects such as extrapyramidal symptoms (e.g., akathisia, dystonia, parkinsonism), weight gain, and metabolic syndrome. Specific medications like clozapine, although effective, can cause significant side effects including agranulocytosis, myocarditis, and seizures, necessitating careful monitoring. Dopamine receptor agonists, like the dopamine 1 partial agonist CVL-562 being studied, aim to target cognitive impairments with potentially fewer side effects, but comprehensive data on their side effect profiles are still being established.

What prior FDA approvals exist?

The FDA has approved several antipsychotic medications for the treatment of Schizophrenia Spectrum Disorder. First-generation antipsychotics, such as haloperidol and chlorpromazine, primarily target dopamine D2 receptors. Second-generation antipsychotics, including risperidone, olanzapine, and aripiprazole, also target dopamine receptors but with a broader mechanism of action, often affecting serotonin receptors as well. Aripiprazole is notable for its partial agonist activity at dopamine D2 and serotonin 5-HT1A receptors, which is somewhat similar to the mechanism being studied with CVL-562, a dopamine 1 partial agonist. These medications aim to manage symptoms and improve the quality of life for individuals with schizophrenia.

What other types of research exist?

Promising novel alternatives to CVL-562 for Schizophrenia Spectrum Disorder patients include dihydrexidine (DAR-0100A), a D1 dopamine receptor agonist, which has shown potential in improving working memory. Additionally, second-generation antipsychotics like aripiprazole, olanzapine, and risperidone continue to be viable options due to their efficacy and safety profiles.

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Dopamine Receptor 1 Partial Agonist

Dopamine Receptor Agonist for Schizophrenia

Phase 1 & 2

Waitlist Available

Led By John Krystal, MD

Research Sponsored by Yale University

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Between the ages of 18 (including 18 years of age) and 45 (up to 45 years and 11 months) at the time of baseline study visit

Be between 18 and 65 years old

Must not have

History of allergy or other contraindication to the proposed pharmacotherapy

History of significant cardiac disease (ex: ischemia, arrhythmia)

Timeline

Screening 3 weeks

Treatment Varies

Follow Up up to two hours for each fmri session.

Summary

This trial tests CVL-562, a new medicine that helps activate brain receptors related to dopamine, in patients with early episode schizophrenia who have memory problems. The goal is to see if it can improve their thinking and memory by enhancing brain activity.

Who is the study for?

This trial is for individuals aged 18-45 with early episode schizophrenia, schizoaffective disorder, or schizophreniform disorder. They must be fluent in English, not pregnant or planning to become so during the study, and on stable psychiatric medication for at least two months. Participants should have no significant medical conditions that could interfere with the study.

What is being tested?

The trial is testing CVL-562 (PF-06412562), a dopamine receptor partial agonist at different doses (1 mg, 4 mg, 15 mg, and 25 mg) against a placebo. It aims to see if this drug can improve working memory by engaging certain brain receptors using neuroimaging as a measure of effectiveness.

What are the potential side effects?

Potential side effects are not explicitly listed but may include typical reactions associated with central nervous system drugs such as headaches, dizziness, nausea, restlessness or other changes in mood or behavior.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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I am between 18 and 45 years old.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I am allergic or react badly to certain medications.

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I have a history of serious heart problems.

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I am currently taking olanzapine, clozapine, ziprasidone, or asenapine.

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I have not had major brain injuries, epilepsy, or severe head trauma.

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I have hepatitis B or C and abnormal liver tests.

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I have HIV/AIDS affecting my cognitive abilities.

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I have not had ECT or neurostimulation in the last 6 months and don't plan to start during the study.

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I am currently experiencing a severe episode of depression or mania.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ up to two hours for each fmri session.

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~up to two hours for each fmri session.

This trial's timeline: 3 weeks for screening, Varies for treatment, and up to two hours for each fmri session. for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Neural activity across brain regions during a spatial working memory (sWM) task.

Secondary study objectives

Association between neural activity and task performance

Functional connectivity across brain regions with the fronto-parietal network during sWM task

Performance during spatial working memory (sWM) task

+3 more

Trial Design

5Treatment groups

Experimental Treatment

Placebo Group

Group I: CVL-562 (PF-06412562) 4 mgExperimental Treatment1 Intervention

Each subject will complete 5 test visits each involving the administration of CVL-562 (PF-06412562) (at different doses) or placebo. Subjects will be randomized to the order of doses of CVL-562 (PF-06412562) (1 mg, 4 mg, 15 mg, or 25 mg) or placebo for the next 5 visits. The randomization will assign 75% of patients to the highest dose on the last visit and 25% would receive the highest dose on one of the other four visits. Only the highest dose (25 mg) will be subject to this pseudo-randomization strategy; all other doses will be randomly distributed.

Group II: CVL-562 (PF-06412562) 25 mgExperimental Treatment1 Intervention

Group III: CVL-562 (PF-06412562) 15 mgExperimental Treatment1 Intervention

Group IV: CVL-562 (PF-06412562) 1 mgExperimental Treatment1 Intervention

Group V: PlaceboPlacebo Group1 Intervention

0 / 9Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Common treatments for Schizophrenia Spectrum Disorder primarily target dopamine receptors, with a focus on D2 receptor antagonists, which help reduce positive symptoms like hallucinations and delusions by blocking dopamine activity. However, these treatments often do not address cognitive impairments and negative symptoms. Novel treatments, such as the dopamine 1 partial agonist CVL-562, aim to modulate D1 receptors, which are crucial for cognitive functions and working memory. By targeting D1 receptors, these treatments hold promise for improving cognitive deficits and overall functional outcomes in patients, addressing a significant unmet need in schizophrenia care.

High dose antipsychotic polypharmacy and dopamine partial agonists - time to rethink guidelines?The past and future of novel, non-dopamine-2 receptor therapeutics for schizophrenia: A critical and comprehensive review.Dopamine Targeting Drugs for the Treatment of Schizophrenia: Past, Present and Future.