Substance Abuse Main Driver of Violence in Schizophrenia, Psychoses

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August 31, 2009 — An excess risk for violence and violent crime, including homicide, in individuals with schizophrenia
and other psychoses is not primarily attributable to the mental illness itself, but rather to comorbid substance abuse, a
new meta-analysis suggests.
The systematic review, which is the first of its kind, looked at 20 studies comparing the risk for violence or violent crime
in individuals with schizophrenia and other psychoses and in that in the general population. In all, there were 18,423
patients with schizophrenia and other psychoses and 1,714,904 individuals from the general population.
“The main reason we undertook this meta-analysis, which includes all of the studies that look at this issue to date, is
because there has been a great deal of uncertainty about whether the relationship between violence and schizophrenia
is causal or related to other factors,” study investigator Martin Grann, PhD, from the Centre for Violence Prevention,
Karolinska Institutet, in Stockholm, Sweden, told Medscape Psychiatry.
“When you look at these 20 studies combined, the pattern is clear that in people with schizophrenia with no alcohol or
drug misuse, the risk of violence is insignificant compared with the general population. But when alcohol and drug
abuse are added to the equation, then you have a problem,” added Dr. Grann.
The study was published online August 11 in PloS Medicine.
People With Schizophrenia Not Dangerous
Among individuals with schizophrenia and other psychoses, 1832 (9.9%) were violent; among the general population,
27,185 (1.6%) were violent. When pooled data from the 2 groups were compared, researchers found that men with
schizophrenia had a pooled odds ratio for violence ranging from 1 to 7, compared with those without mental illness.
In women, the odds ratio for violence ranged from 4 to 29 in those with schizophrenia and other psychoses, compared
with their counterparts without mental illness.

The effects of comorbid substance abuse was marked with the random-effects odds ratios of 2.1 without comorbidity
and an odds ratio of 8.9 with comorbidity, the authors report. Importantly, said Dr. Grann, risk estimates of violence in
individuals with substance abuse but without psychosis were similar to those in individuals with psychosis and
comorbid substance abuse. The risk for homicide was increased in individuals with psychosis — with or without
comorbid substance abuse.
Dr. Grann described the increased risk for violence and homicide among individuals with severe mental illness without
substance abuse as “very modest,” compared with the general population.
“People with schizophrenia are not dangerous. Individuals without schizophrenia with drug and alcohol abuse are more
likely to be violent than individuals with schizophrenia who also have abuse problems. In other words, if a person is an
alcoholic or a drug addict, he is less likely to be violent if he also has schizophrenia. So, in this context, you could say
schizophrenia is actually protective,” said Dr. Grann.
This review, he added, highlights the “critical need” for clinicians to address issues of substance and alcohol abuse in
this patient population, an issue he said is often neglected.

Lack of Integrated Care
Asked by Medscape Psychiatry to comment on the findings, Jeffrey A. Lieberman, MD, Lawrence E. Kolb professor
and chair of psychiatry at the Columbia University College of Physicians and Surgeons and director of the New York
State Psychiatric Institute in New York City, agreed that the study underlines the importance of addressing substance
abuse in these patients.
He agreed with Dr. Grann that current management of substance abuse in patients with severe mental illness is not
optimal. One of the barriers to effective treatment in the United States, said Dr. Lieberman, is a lack of integrated care.
“Diagnosis is not really a problem. However, as far as treatment is concerned, there is a systemic problem because
frequently substance-abuse treatment isn’t available in mental healthcare clinical settings, and vice versa. This makes
it difficult to provide a broad array of treatments in a single clinical setting, and it is similarly difficult to get patients to go
to 2 separate centers for treatment, “he said.
One of the study’s limitations, said Dr. Lieberman, is the fact that it did not examine the issue of treatment adherence,
which can be a risk factor for violence.
“The features that tend to characterize violence in patients with mental illness are psychotic disorders, treatment
nonadherence, and substance abuse. Another influencing factor is homelessness, but the triad of psychotic illness,
treatment nonadherence, and comorbid substance abuse point to the highest risk for violent behavior in mentally ill
people,” he said.
Both Drs. Grann and Lieberman said that more research is needed to determine whether treatments used to address a
primary diagnosis of substance abuse are effective in individuals with psychosis who have comorbid substance abuse,
and whether such treatments lower the risk for violence.
The researchers have disclosed no relevant financial relationships.

FROM: Medscape Medical News

BY: Caronline Cassels

A Randomized Placebo-Controlled Clinical Trial of 5 Smoking Cessation Pharmacotherapies

This paper presents the first head-to-head comparison of five commonly used, effective smoking cessation
pharmacotherapies. It shows that all are effective when compared with placebo but that the combination of
nicotine patch plus nicotine lozenge was the most effective relative to placebo. These results provide
important information for clinicians who are trying to choose among the available smoking cessation
therapies, and call for a similar study that includes varenicline.
Among all addictive substances, cigarette smoking causes the highest morbidity and mortality rates. A number of
medications have been shown to be effective in helping smokers quit, but studies have typically compared one
pharmacotherapy with placebo, leaving the clinician with little evidence about which pharmacotherapy is the most
effective. This study begins to fill that gap by presenting data from a head-to-head comparison of nicotine lozenge,
nicotine patch, sustained-release bupropion, nicotine patch plus nicotine lozenge, bupropion plus nicotine lozenge,
and placebo. The study included 1504 adults who smoked at least 10 cigarettes/day during the past 6 months and
were interested in quitting, agreed to participate in the study, and had no medical or psychiatric contraindications for
any of the pharmacotherapies. Pharmacotherapies were delivered for 8-12 weeks, depending on the specific
medication and according to current treatment guidelines, and study participants received six smoking cessation
counseling sessions. At 6 months, 22% of placebo patients had carbon dioxide-confirmed abstinence compared to
40.1% of ‘patch plus lozenge’ patients, with the other therapies producing abstinence rates of 31.8% to 33.4%.
Placebo response rates were higher than usual, possibly due to the counseling and motivation needed to
participate, and all therapies were generally well tolerated. It would be very interesting and important to conduct a
similar study that includes varenicline.

FROM: Faculty of 1000 Medicine

BY: George Woody

Metabolic Monitoring in Patients Taking Second-Generation Antipsychotics Remains Poor

January 6, 2010 (Updated January 7, 2010) — When it comes to monitoring metabolic effects of second-
generation antipsychotics (SGAs), it appears that physicians are not heeding recommendations by government or
leading professional organizations. New research suggests that less than one-third of patients treated with these
medications, which can have significant and serious adverse metabolic effects, undergo blood glucose or lipid
testing.
“We studied a 3 state population of Medicaid recipients and found diabetes and dyslipidemia screening among
patients receiving SGAs was low and did not increase following the FDA [Food and Drug Administration] warnings or
recommendations from the American Diabetes and American Psychiatric Associations, which called for increased
metabolic monitoring of patients taking these agents,” study investigator Elaine H. Morrato, DrPH, MPH, University
of Colorado, Denver, told Medscape Psychiatry.
The retrospective analysis is published in the January issue of Archives of General Psychiatry.
Prompted by research showing a strong link between SGAs and an increased risk for hyperglycemia and diabetes,
starting in 2003 the FDA began requiring warning labels on SGAs, including olanzapine, risperidone, quetiapine,
ziprasidone, clozapine and aripriprazole.
“In some cases the hyperglycemia was extreme and associated with ketoacidosis, hyperosmolar coma, or death,”
the study authors note.
As part of the FDA initiative, manufacturers of SGAs were required to send letters to neuropsychiatric health care
professionals informing them of the warnings and advising them of the need for glucose testing in patients with a
diagnosis of diabetes, risk factors for diabetes, or symptoms of hyperglycemia.
At the same time, the American Diabetes Association and the American Psychiatric Association published a
consensus statement describing the metabolic risks associated with atypical antipsychotics and specifying a
monitoring protocol for all patients receiving these medications.
Low Rates of Metabolic Testing
To assess the impact of these warnings and recommendations on glucose and lipid testing and drug selection of
SGAs, the investigators examined laboratory claims data from the Medicaid population of 3 states — California,
Missouri, and Oregon — between 2002 and 2005.
They compared rates of metabolic monitoring between a group of 109,451 patients receiving SGAs and a control
group of 203,527 patients who began taking albuterol but who did not receive antipsychotic medication. Rates were
also compared before and after the FDA warning.
Baseline glucose and lipid testing rates for SGA-treated patients were low at 27% and 10%, respectively. However,
the FDA warning was not associated with an increase in glucose testing among SGA-treated patients, and lipid
testing rates only increased by a marginal 1.7%.

FROM: Medscape Medical News

BY: Caroline Cassels

Psychotropic Drugs Up-regulate the Expression of Cholesterol Transport Proteins Including ApoE in Cultured Human CNS- and Liver Cells

Background:

Disturbances in lipid homeostasis and myelination have been proposed in the pathophysiology of
schizophrenia and bipolar disorder. We have previously shown that several antipsychotic and antidepressant drugs
increase lipid biosynthesis through activation of the Sterol Regulatory Element-Binding Protein (SREBP)
transcription factors, which control the expression of numerous genes involved in fatty acid and cholesterol
biosynthesis. The aim of the present proof-of-principle study was to investigate whether such drugs also affect lipid
transport and export pathways in cultured human CNS and liver cells.
Results:

Quantitative PCR and immunoblotting were used to determine the level of lipid transport genes in human
glioblastoma (GaMg) exposed to clozapine, olanzapine, haloperidol or imipramine. The effect of some of these
drugs was also investigated in human astrocytoma (CCF-STTG1), neuroblastoma (SH-SY5Y) and hepatocellular
carcinoma (HepG2) cells. We found significant transcriptional changes of cholesterol transport genes (ApoE,
ABCA1, NPC1, NPC2, NPC1L1), which are predominantly controlled by the Liver X receptor (LXR) transcription
factor. The up-regulation was observed after 24 to 48 hours of drug exposure, which is markedly delayed as
compared to the drug-induced SREBP-controlled stimulation of lipid biosynthesis seen after 6 hours.
Conclusion: Our data show that stimulation of cellular lipid biosynthesis by amphiphilic psychotropic drugs is
followed by a transcriptional activation of cholesterol transport and efflux pathways. Such effects may be relevant for
both therapeutic effects and metabolic adverse effects of psychotropic drugs.
Background
Antipsychotic and antidepressant drugs are imperative in the treatment of schizophrenia and affective disorders.
These drugs exert their therapeutic effects at least in part through perturbation of the dopamine-, noradrenaline- and
serotonin neurotransmitter systems in the brain, but additional molecular mechanisms of action are likely to
contribute to their clinical effect. We have demonstrated that several antipsychotics and antidepressants increase
lipid biosynthesis in cultured human CNS cells.[1–4] This drug-induced stimulation of cellular lipogenesis could
represent a novel mechanism of psychotropic drug action in the brain, since glia-produced lipids, including
cholesterol, play important roles in myelination and synaptogenesis.[5,6] Interestingly, several studies have indicated
disrupted glial function, as well as lipid and myelin abnormalities, in schizophrenia and affective disorders.[7–11] The
drug-mediated lipogenic effect could also be relevant for the associated serious metabolic adverse effects, such as
weight gain and dyslipidemia. Indeed, some of the psychotropic drugs increase the expression of lipid biosynthesis
genes in cultured hepatocytes and adipocytes,[1,3,12–14] as well as in blood cells from olanzapine-treated patients.[15]
The increased lipid biosynthesis is mediated through activation of the sterol regulatory element-binding protein
(SREBP) transcription factors, which control the expression of genes involved in cellular production of cholesterol
(e.g., 3-hydroxy-3-methylglutaryl-CoA reductase; HMGCR) and fatty acids (e.g., fatty acid synthase; FASN and
stearoyl CoA-desaturase; SCD). The SREBP system is sensitive to cationic amphiphilic drugs, such as antipsychotic
and tricyclic antidepressant, through their ability to partly mimic the effects of oxysterols.[16]

FROM: BMC Pharmacology

By: Audun O Vik-Mo; Johan Fernø; Silje Skrede; Vidar M Steen

Improving the Quality of Mental Health Care

Objective.

To develop international guidance for improving the quality of mental health care in low- and middle-
income countries.
Design.

A panel developed recommendations based on a comprehensive literature review, consultation with over
100 experts from 46 countries and an analysis of international best practices.
Recommendations. A 5-pronged approach to improving the quality of mental health care is recommended. Quality
improvement requires the alignment of policy and legislation with the attainment of good quality mental health
outcomes. Key partners must be brought into the quality improvement process. Funding can be an important tool for
promoting good quality but needs to be correctly aligned to meet policy objectives and to promote evidence-based
interventions. Accreditation procedures and quality standards need to be carefully developed and resources
allocated for their implementation. Finally, quality improvement must be brought into routine service management
and delivery.
Conclusions.

Through a systematic approach to quality improvement, it is possible to ensure that the best possible
interventions are provided within the constraints of each country and that the rights and well-being of people with
mental disorders is optimally promoted. Quality improvement is not a luxury but an integral part of ensuring that the
best possible services are provided to all who need them.

Introduction
Poor quality mental health services can violate basic human rights, lead to negative therapeutic outcomes and
prevent people from enjoying the highest standard of physical and mental health.[1] However, poor quality of care
can be substantially redressed through concerted and systematic quality improvement strategies.[2] Evidence is now
emerging that the very substantial burden of disease attributable to mental disorder can be significantly reduced
through high-quality evidence-based mental health care.[3] While prescribing methods for improving the quality of
mental health services is challenging, not least because there is tremendous variation in the availability of financial
and human resources in different countries, providing guidance to countries to assist them to attain better quality
mental health care is necessary and important.

What is Meant by Quality?

Quality in health care has been defined by the Institute of Medicine as ‘the degree to which health care services for
individuals and populations increase the likelihood of desired health outcomes and are consistent with current
professional knowledge’.[4] Quality may be viewed from a number of perspectives. For a person with a mental
disorder, quality can mean reduction in symptoms, being able to carry on with ‘normal’ life and being treated with
dignity and with full respect of his/her rights to autonomy and independent decision-making. From the point of view
of a family member, quality may mean being provided with support to help cope with some of the emotional
consequences of having an ill family member and being provided with the information and skills to actively assist a
family member’s integration into the community. A service provider on the other hand may see quality as ensuring
that patients receive the best treatment and care available. For a policy-maker, quality can be seen as the key to
improving the mental health of the population, ensuring value for money expended and accountability. All of these
perspectives are important; in this article, we primarily examine quality from the perspective of public health service

FROM: International Journal for the Quality of Health Care

By: M. Funk; C. Lund; M. Freeman; N. Drew

Blood Test For Schizophrenia Could Be Ready This Year

This article is breaking and important news.  Sabine Bahn the British researcher who developed the test has been working on this test and been featured in news article for some time.  The partner who is commercializing the test is Rules Based Medicine.  They have recently been hiring high level executives from pharmaceutical companies with expertise in marketing to market this product.  Rules Based Medicine is also in the midst of becoming a publicly traded company and issuing stock to raise money for this and other bio marker tests they are working on.  Although this article mentions only schizophrenia they are also working on one for Bipolar as well.

Medical News Today

Submitted by: Darrell H.

Many Doctors Basically Ignored FDA Warning

The following is a link to a study on how well doctors followed up on an FDA warning about monitoring patients for side effects of atypical antipsychotics.  It found that little changed in treatment practices after the warning was issued.

Science Daily

Submitted by: Darrell H.

The Wrong Story About Depression

Below is a follow up article from the New York Times about last weeks big news story that antidepressants are not effective for mild depression.  It notes that there is a lot more to the story than was covered by the news media last week.

New York Times

Submitted by: Darrell H. –with thanks to a friend from his emailing list

Antidepressants Work For Severe, Not Mild, Depression

The following is an article from the Wall Street Journal about antidepressants.
Wall Street Journal

Submitted by: Darrell H.

The Brain’s Glue — How It Affects Brain Function

The following is a link to a New Hampshire Public Radio program on brain cells known as glia or the brain’s glue.

These cells represent about 85% of the tissue in the brain and recent research has shown they have a significant role in brain function.  The program mentions briefly impacts on dementia, alzheimers, schizophrenia, depression, and addiction.  To listen to the program click on one of the links after listen at the upper left of the web page.  The program lasts approximately 10 minutes.

New Hampshire Public Radio

Submitted by: Darrell H.