This Phase I/IIa Proof-of-Concept (PoC) trial is designed to assess the effect of adding a single and repeated low dose (15mg/d) of pipamperone (PIP) for 6 weeks to stable treatment with an effective dose of risperidone (RIS) or paliperidone (PAL) on functional MRI tests and clinical outcome of chronic schizophrenic patients with residual, so-called 'positive' symptoms, as well as on cognition, motivation, subjective well-being of patients, negative symptoms, general psychopathological symptoms and safety/tolerability.

This exploratory study of 7 weeks was intended to be performed in 40 to 60 patients in up to 10 centers in Belgium. In a subset of patients, the 6-week treatment phase will be preceded by a single-dose cross-over phase with 1 week of wash-out. While the objective of the study, due to its exploratory design, is to assess any effect of the study medication on MRI or clinical outcome, the study medication is expected to improve the residual (remaining) positive symptom(s) of patients. In addition, genetic and pharmacokinetic testing may be performed to learn more about the disorder and its treatment.

Inclusion Criteria:

• Patient is informed and given ample time and opportunity to think about her/his participation and has given her/his written informed consent.
• Patient understands the investigational nature of the trial and is willing and able to comply with the trial requirements.
• Patient is male or female, aged 18-65 years.
• Patients has Schizophrenia or Schizoaffective disorder according to the Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV-R criteria. Diagnosis will be confirmed by the Mini International Neuropsychiatric Interview (MINI)
• Patient is being treated during at least 12 weeks with a stable dosage of either risperidone depot of 12.5-50mg IM every 2 weeks, paliperidone depot of 25-100mg IM every 4 weeks, risperidone oral administration of 2-6 mg/d, or paliperidone oral administration of 4-12 mg/d
• Patient has a CGI-S score of 3 (mildly ill) or more at baseline.
• Patient has a score of 4 or more on at least 1 item of the positive PANSS subscale (residual symptoms).

Exclusion Criteria:

• Acute exacerbation of schizophrenic or schizoaffective disorder during the past 12 weeks.
• Documented debility or an IQ below 85.
• Comorbid axis 1 conditions (including anxiety disorders, eating disorders, impulse control disorders) requiring drug treatment over the previous 12 weeks.
• Patient has taken, in the past 6 weeks prior to randomization, any newly initiated psychoactive drug.
• Patient was withdrawn from psychoactive drug treatment in the past week or within a period shorter than 5x the elimination half-life of any psychoactive drug. Withdrawal of any prior antipsychotic treatment should not have occurred within 6 weeks prior to baseline.
• Concomitant treatment with any additional antipsychotic drug at a therapeutic dosage, diuretics, QT prolongation drugs, or dopamine agonists.
• Formal cognitive psychotherapy initiated during study treatment or within 6 weeks prior to randomization.
• Patient has any other medical or psychiatric condition, which in the opinion of the investigator, can jeopardize or would compromise the patient's ability to participate in this trial or that would interfere with trial assessments.
• Patient with a DSM-IV alcohol or substance dependence diagnosis (within the last 6 months), an alcohol or substance abuse diagnosis (within the last month) or having a positive standard screen for alcohol or drugs (including benzodiazepines and opioids).
• 'Any concomitant psychoactive treatment (including psychotherapy)' or 'Patient received, in the 6 weeks prior to randomization any newly prescribed psychoactive drug'.
• Patient is pregnant, nursing, or is a woman of child-bearing potential who is not surgically sterile, 2 years postmenopausal, or who does not consistently use 2 combined effective methods of contraception (including at least 1 barrier method), unless sexually abstinent.