Clinical trial NCT01567124: Alleviating the Metabolic Side Effects of Antipsychotic Medications
Official title: A Randomised Trial Examining the Effectiveness of Sympathetic Nervous Inhibition in Alleviating the Metabolic Side Effects of Antipsychotic Medications in Patients With Schizophrenia
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE4
Conditions: Schizophrenia
Keywords: Schizophrenia
Moxonidine
Sympathetic nervous system activation
Cardiometabolic side effects of antipsychotics
Lead sponsor: Baker Heart and Diabetes Institute
Sponsor class: OTHER
Collaborators: name: The Alfred
name: Monash Medical Centre
name: Ballarat Health Services
First posted: 2012-03-30
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The use of antipsychotic medications has increased over the past decade. While more recently developed medications are improved with regards to extrapyramidal side effects, the use of atypical antipsychotics has been associated with substantial weight gain and a worsening of metabolic profile. The time course and extent of weight gain differs among antipsychotics, with olanzapine and clozapine being associated with greatest weight gain.

Mechanisms underlying a worsening metabolic profile, obesity and obesity-related illnesses are complex, extending beyond sedentary lifestyle, poor diet and genetic predisposition. There is also a growing body of evidence that the sympathetic nervous system (SNS) has a role in the generation of both obesity and obesity-related illness. While the role of the SNS in blood pressure control is readily acknowledged it is less well appreciated that activation of the SNS exerts profound metabolic effects.

Although the fact of a causal relation linking antipsychotic drugs and obesity is unequivocally established, the biological mechanisms operating are unclear, and strategies for preventive therapy remain largely unformulated.

This study aims to investigate the role of the SNS and its association with the metabolic abnormalities that are frequently observed in patients with schizophrenia following treatment with antipsychotic medications.

Additionally, the study will investigate whether treatment with the centrally acting sympatholytic agent moxonidine will modify SNS activity and, hence, favourably influence the downstream metabolic abnormalities seen in antipsychotic treated patients with schizophrenia.

Hypothesis 1: Elevated sympathetic nervous system activity underlies the metabolic disturbances observed in patients following antipsychotic therapy.

Aim 1: To investigate the role of the sympathetic nervous system and its association with the metabolic abnormalities that are frequently observed in patients with schizophrenia following treatment with antipsychotic medications

Hypothesis 2: Central sympathoinhibition with moxonidine will blunt the elevated sympathetic nervous activity and downstream metabolic abnormalities observed in antipsychotic treated patients with schizophrenia.

Aim 2: Determine whether treatment with the centrally acting sympatholytic agent moxonidine will modify sympathetic nervous system activity and, hence, favourably influence the downstream metabolic abnormalities seen in antipsychotic treated patients with schizophrenia.


Eligibility criteria: Inclusion Criteria:

* Aged 18-65 years.
* Capable of understanding and willing to provide signed and dated written, voluntary informed consent in advance of any protocol-specific procedures.
* Psychiatrist confirmed diagnosis of schizophrenia.
* Stabilised on clozapine or olanzapine for at least 6 weeks.
* 5% increase in body weight since commencement of clozapine or olanzapine.

Exclusion Criteria:

* Aged \< 18 or \> 65 years.
* On a Community Treatment Order (CTO).
* Comorbid mental health conditions including schizoaffective disorder, personality disorders, eating disorders, mental retardation, pervasive developmental disorder, delirium, dementia (ie, Mini Mental State Examination \[MMSE\] \< 23), and amnesia.
* Concurrent treatment with two or more antipsychotics (including clozapine or olanzapine) at screening.
* Concomitant treatment with sedatives, tricyclic antidepressants, metformin, insulin or beta adrenergic blocking agents.
* Known or suspected hypersensitivity to moxonidine.
* Previous history of clozapine induced myocarditis.
* Pre-existing and/or current diagnosed heart disease.
* Comorbid medical conditions including medicated hypertension, bradycardia (heart rate \< 50 beats/min), type 1 diabetes, epilepsy, bleeding disorders, alcohol/drug dependence, infectious blood diseases, and moderate-severe renal impairment.
* Clinically significant abnormalities on examination or laboratory testing, and clinically significant medical conditions not listed above that are serious and/or unstable.
* Pregnant or breastfeeding women.
* Women of childbearing potential (WOCP) who are not using medically accepted contraception (ie, intrauterine devices \[IUDs\], hormonal contraceptives \[oral, depot, patch or injectable\], and double barrier methods such as condoms or diaphragms with spermicidal gel or foam. Women who are postmenopausal (ie, amenorrhea for at least 12 consecutive months) or surgically sterile are not considered to be WOCP.
* Sexually active men with WOCP partners who are not using medically accepted contraception.

Primary outcomes:
measure: To determine the association between sympathetic nervous system and metabolic abnormalities (eg, weight gain) observed with antipsychotic treatment.
timeFrame: Baseline and following 12 weeks of moxonidine/placebo treatment.
Secondary outcomes:
measure: Change from baseline in sympathetic nervous system activity.
timeFrame: Baseline and following 12 weeks of moxonidine/placebo treatment.
Other outcomes:
Locations:
city: Ballarat
country: Australia
facility: Ballarat Health Service Psychiatric Services
state: Victoria
city: Clayton
country: Australia
facility: Monash Medical Centre - Monash Health
state: Victoria
city: Melbourne
country: Australia
facility: Alfred and Baker Medical Unit - Alfred Hospital
state: Victoria
city: Melbourne
country: Australia
facility: Baker IDI Heart & Diabetes Institute
state: Victoria
Study officials:
affiliation: Baker IDI Heart & Diabetes Institute
name: Gavin Lambert
role: STUDY_DIRECTOR
affiliation: Monash Medical Centre
name: David Barton
role: PRINCIPAL_INVESTIGATOR
affiliation: Ballarat Health Services
name: Abdul Khalid
role: PRINCIPAL_INVESTIGATOR
References: