• Proportion of responders at week 3 [ Time Frame: Week 3 ]
  Proportion of participants with >30% reduction from baseline in the Salpetriere Retardation Rating Scale (SRRS)
• Change in Salpetriere Retardation Rating Scale (SSRS) from baseline [ Time Frame: Week 3, week 6, week 24 ]
  Change in the Salpetriere Retardation Rating Scale (SRRS) from baseline; the total score of 15 items is used, ranging 0-60 with higher scores indicating worse outcome

• Proportion of responders at week 3 [ Time Frame: Week 3 ]
  Proportion of participants with >30% reduction from baseline in the Salpetriere Retardation Rating Scale (SRRS)
• Change in Salpetriere Retardation Rating Scale (SSRS) from baseline [ Time Frame: Week 3 ]
  Change in the Salpetriere Retardation Rating Scale (SRRS) from baseline

• Change in catatonia severity from baseline to week 3 [ Time Frame: Week 3, week 6, week 24 ]
  Observer based rating of catatonia severity with the Bush Francis Catatonia Rating Scale (BFCRS), assessment blind to intervention, total score of the BFCRS is used ranging 0-69 , with higher scores indicating poorer outcome
• Change in negative symptoms from baseline [ Time Frame: Week 3, week 6, week 24 ]
  Change in the Brief Negative Symptom Scale (BNSS) from baseline, total score is used, ranging from 0-78 with higher values indicating poorer outcome, i.e. more negative symptom severity
• Change in psychosis severity from baseline [ Time Frame: Week 3, week 6, week 24 ]
  Change in the Positive And Negative Symptom Scale (PANSS) from baseline, PANSS total score assesses the severity of positive, negative and general symptoms, ranging from 30-210 with higher scores indicating increased symptom severity, i.e. poorer outcome
• Change in physical activity self report from baseline [ Time Frame: Week 3, week 6, week 24 ]
  Change in the International Physical Activity Questionnaire (IPAQ), the total score is used ranging from 0-70000 metabolic equivalent (MET)
• Change in objectively measured physical activity from baseline [ Time Frame: Week 3, week 6, week 24 ]
  Change in the activity levels using wrist actigraphy
• Change in dexterity from baseline [ Time Frame: Week 3, week 6, week 24 ]
  Change in the coin rotation task from baseline
• Change in cortical excitability of the motor cortex from baseline [ Time Frame: Week 3, week 6, week 24 ]
  Change in Short Interval Cortical Inhibition (SICI) from baseline
• Change in social and community functioning [ Time Frame: Week 3, week 6, week 24 ]
  Change in Social and Occupational Functional Assesment Scale (SOFAS) from baseline, the score ranges from 0-100 with higher scores indicating better functioning, i.e. better outcome
• Change in functional capacity [ Time Frame: Week 3, week 6, week 24 ]
  Change in the Score of the brief version of the University of California, San Diego, Performance-Based Skills Assessment (UPSA-brief) assessment from baseline, higher scores indicating better function, the total score is used ranging 0-100
• Change in functional connectivity [ Time Frame: Week 3 ]
  Change in the resting state functional connectivity within the cerebral motor system based on functional magnetic resonance imaging scans from baseline
• Change in resting state cerebral perfusion [ Time Frame: Week 3 ]
  Change in the resting state cerebral perfusion within the cerebral motor system based on functional magnetic resonance imaging scans from baseline

• Change in SSRS from baseline [ Time Frame: Week 6 ]
  Change in the Salpetriere Retardation Rating Scale (SRRS) from baseline
• Change in SSRS from baseline [ Time Frame: Week 24 ]
  Change in the Salpetriere Retardation Rating Scale (SRRS) from baseline
• Change in catatonia severity from baseline to week 3 [ Time Frame: Week 3 ]
  Observer based rating of catatonia severity with the Bush Francis Catatonia Rating Scale, assessment blind to intervention
• Change in catatonia severity from baseline to week 6 [ Time Frame: Week 6 ]
  Observer based rating of catatonia severity with the Bush Francis Catatonia Rating Scale, assessment blind to intervention
• Change in catatonia severity from baseline to week 24 [ Time Frame: Week 24 ]
  Observer based rating of catatonia severity with the Bush Francis Catatonia Rating Scale, assessment blind to intervention
• Change in negative symptoms from baseline [ Time Frame: Week 3 ]
  Change in the Brief Negative Symptom Scale (BNSS) from baseline
• Change in negative symptoms from baseline [ Time Frame: Week 6 ]
  Change in the Brief Negative Symptom Scale (BNSS) from baseline
• Change in negative symptoms from baseline [ Time Frame: Week 24 ]
  Change in the Brief Negative Symptom Scale (BNSS) from baseline
• Change in psychosis severity from baseline [ Time Frame: Week 3 ]
  Change in the Positive And Negative Symptom Scale (PANSS) from baseline
• Change in psychosis severity from baseline [ Time Frame: Week 6 ]
  Change in the Positive And Negative Symptom Scale (PANSS) from baseline
• Change in psychosis severity from baseline [ Time Frame: Week 24 ]
  Change in the Positive And Negative Symptom Scale (PANSS) from baseline
• Change in physical activity self report from baseline [ Time Frame: Week 3 ]
  Change in the International Physical Activity Questionnaire (IPAQ)
• Change in physical activity self report from baseline [ Time Frame: Week 6 ]
  Change in the International Physical Activity Questionnaire (IPAQ)
• Change in physical activity self report from baseline [ Time Frame: Week 24 ]
  Change in the International Physical Activity Questionnaire (IPAQ)
• Change in objectively measured physical activity from baseline [ Time Frame: Week 3 ]
  Change in the activity levels using wrist actigraphy
• Change in objectively measured physical activity from baseline [ Time Frame: Week 6 ]
  Change in the activity levels using wrist actigraphy
• Change in objectively measured physical activity from baseline [ Time Frame: Week 24 ]
  Change in the activity levels using wrist actigraphy
• Change in dexterity from baseline [ Time Frame: Week 3 ]
  Change in the coin rotation task from baseline
• Change in dexterity from baseline [ Time Frame: Week 6 ]
  Change in the coin rotation task from baseline
• Change in dexterity from baseline [ Time Frame: Week 24 ]
  Change in the coin rotation task from baseline
• Change in cortical excitability of the motor cortex from baseline [ Time Frame: Week 3 ]
  Change in Short Interval Cortical Inhibition (SICI) from baseline
• Change in cortical excitability of the motor cortex from baseline [ Time Frame: Week 6 ]
  Change in Short Interval Cortical Inhibition (SICI) from baseline
• Change in cortical excitability of the motor cortex from baseline [ Time Frame: Week 24 ]
  Change in Short Interval Cortical Inhibition (SICI) from baseline
• Change in social and community functioning [ Time Frame: Week 3 ]
  Change in Social and Occupational Functional Assesment Scale (SOFAS) from baseline
• Change in social and community functioning [ Time Frame: Week 6 ]
  Change in Social and Occupational Functional Assesment Scale (SOFAS) from baseline
• Change in social and community functioning [ Time Frame: Week 24 ]
  Change in Social and Occupational Functional Assesment Scale (SOFAS) from baseline
• Change in functional capacity [ Time Frame: Week 3 ]
  Change in the Score of the brief version of the University of California, San Diego, Performance-Based Skills Assessment (UPSA-brief) assessment from baseline
• Change in functional capacity [ Time Frame: Week 6 ]
  Change in the Score of the UPSA-brief assessment from baseline
• Change in functional capacity [ Time Frame: Week 24 ]
  Change in the Score of the UPSA-brief assessment from baseline
• Change in functional connectivity [ Time Frame: Week 3 ]
  Change in the resting state functional connectivity within the cerebral motor system based on functional magnetic resonance imaging scans from baseline
• Change in resting state cerebral perfusion [ Time Frame: Week 3 ]
  Change in the resting state cerebral perfusion within the cerebral motor system based on functional magnetic resonance imaging scans from baseline

As psychomotor slowing is a major problem in schizophrenia, contributing to poor functional outcome, and as no current treatment is effectively targeting psychomotor slowing, this study seeks to test noninvasive brain stimulation to overcome psychomotor slowing. Previous studies documented an aberrant increase of neural activity within the supplementary motor area (SMA) in patients with schizophrenia who had psychomotor slowing. Furthermore, a pilot study in major depression and schizophrenia indicated that inhibitory 1 Hz repetitive transcranial magnetic stimulation (rTMS) would improve psychomotor slowing in 82% of the participants. While this is encouraging, further evidence is needed to 1) replicate the clinical effect of 1 Hz rTMS on the SMA in schizophrenia, 2) to test against sham stimulation, facilitatory stimulation and no intervention, and 3) to test the effects of rTMS on the neural circuitry. Therefore, OCoPS includes more patients, more treatment arms, and more outcome variables than the first pilot trial.

Here we will enroll 88 patients with schizophrenia spectrum disorders and severe psychomotor slowing according to a standard rating scale. Subjects will be randomized to four arms, three of which are double blinded.

three weeks of daily rTMS over the SMA will be delivered. The first group receives inhibitory 1 Hz rTMS, the second group receives facilitatory intermittent theta burst stimulation (iTBS), and the third group receives sham stimulation with a placebo-coil. The fourth group will have no rTMS during the first three weeks, but will repeat the baseline measures after three weeks and then enter a treatment with 1Hz rTMS for three weeks. Outcome measures include the Salpetriere Retardation Rating Scale, observer ratings of motor behavior as well as measures of functioning. After the interventions, follow-up visits are planned at week 6 and week 24.

Finally, at baseline and after the rTMS course, patients will undergo MRI scanning for structural and functional alterations of the cerebral motor system.

• Schizophrenia and Related Disorders
• Schizophrenia
• Schizoaffective Disorder
• Brief Psychotic Disorder

• Device: 1 Hz rTMS
  1 Hz stimulation at 110% of resting motor threshold over supplementary motor area
• Device: iTBS
  50 Hz theta burst stimulation at 80% of resting motor threshold over supplementary motor area
• Drug: Placebo
  1 Hz stimulation with the placebo TMS coil without any magnetic emission

• Experimental: Inhibitory repetitive transcranial magnetic stimulation (rTMS)
  1 Hz stimulation of 17 mins over the supplementary motor area (SMA), 1000 pulses at 110% resting motor threshold intensity total of 15 sessions in 3 weeks
  Intervention: Device: 1 Hz rTMS
• Active Comparator: Facilitatory intermittent theta burst stimulation (iTBS)

  Intermittent theta burst stimulation of 50 Hz over the supplementary motor area (SMA) with 600 pulses in 2 sec trains every 10 seconds for 190 seconds total. Two iTBS stimulations will be administered with 15 mins pause in between.

  total of 15 sessions in 3 weeks

  Intervention: Device: iTBS
• Placebo Comparator: Placebo
  1 Hz stimulation of 17 mins over the supplementary motor area (SMA) without any magnetic emission using a placebo-coil that looks identical and makes identical sounds as the real TMS coil total of 15 sessions in 3 weeks
  Intervention: Drug: Placebo
• No Intervention: Waiting group
  This group will receive no intervention for 3 weeks. Afterwards they will receive the inhibitory rTMS protocol as in the first arm

Inclusion Criteria:

• Right-handed subjects
• Ability and willingness to participate in the study
• Ability to provide written informed consent
• Informed Consent as documented by signature
• Schizophrenia spectrum disorder according to diagnostic and statistical manual version 5 (DSM-5) criteria with current psychomotor slowing according to the Salpetriere Retardation Rating Scale (SRRS), score >= 15

Exclusion Criteria:

• Substance abuse or dependence other than nicotine
• Past or current medical or neurological condition associated with impaired or aberrant movement, such as brain tumors, stroke, M. Parkinson, M. Huntington, dystonia, or severe head trauma with subsequent loss of consciousness.
• Epilepsy or other convulsions
• History of any hearing problems or ringing in the ears
• Standard exclusion criteria for MRI scanning and TMS; e.g. metal implants, claustrophobia
• Patients only: any TMS treatment in the past 3 months
• Women who are pregnant or breast feeding,
• Intention to become pregnant during the course of the study,
• Female participants who are surgically sterilised / hysterectomised or post-menopausal for longer than 2 years are not considered as being of child bearing potential.
• Previous enrolment into the current study,
• Enrolment of the investigator, his/her family members, employees and other dependent persons
• Controls only: history of any psychiatric disorder or first-degree relatives with schizophrenia spectrum disorders.