Long-term benzodiazepine use is associated with increased mortality in people with schizophrenia

What I did before

When psychiatric patients are treated in an emergency department, they are often hypervigilant, manic, or otherwise in an excited, agitated state. The current standard of care to manage acute agitation in adults is using an antipsychotic medication and a benzodiazepine, often loxapine or haloperidol and lorazepam. For patients who have schizophrenia, antipsychotic medication alone often treats such symptoms in the longer term, yet many patients are discharged with a benzodiazepine prescription continue long-term benzodiazepine use possibly because the community clinician hopes to avoid triggering a relapse in discontinuing the medication. As a psychiatrist who has worked on acute and tertiary inpatient units, I have discharged patients on benzodiazepines with the expectation it would eventually be discontinued, but I have also seen many patients for whom it never was.

What changed my practice

Then, in 2013 while at the 7th Annual Pacific Psychopharmacology Conference, I was introduced to research showing that people with schizophrenia on chronic benzodiazepine therapy have an increased risk for suicide and all-cause mortality. I kept these observations in the back of my mind and was further alarmed in 2016 when another article from the same researchers found high-dose benzodiazepine use, but not lesser doses, was associated with increased suicide and cardiovascular mortality.

What I do now

Based upon these studies, I find the evidence compelling that benzodiazepines are contraindicated for long-term use in people with schizophrenia. When appropriate, I continue to use lorazepam for acute agitation amongst other reasons, I also educate patients about the risk of long-term use, including dependence and cognitive impairment in addition to mortality.To raise awareness of this issue among my colleagues, I mention the rationale and include recommendations for tapering benzodiazepines in consultation reports and discharge summaries.

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Twenty percent of schizophrenia may be treatment-resistant from onset

About 30% of people with schizophrenia do not have adequate response to antipsychotic medications other than clozapine. Treatment-resistant psychosis has no well-established predictors although early-onset psychosis and prolonged duration of untreated psychosis may be risk factors. The Genetics and Psychosis study based in South London, UK, enrolled 283 patients with schizophrenia-spectrum disorders in their first episode who underwent assessments including the Positive and Negative Syndrome Scale, Global Assessment of Functioning, and the Weschler Adult Intelligence Scale. The cohort had follow-up investigations 5 years after first assessment by means of the WHO Life Chart Schedule, intended for documenting the longitudinal course of schizophrenia.

Patients were determined to have treatment-resistant schizophrenia (TRS) if they were either treated with clozapine or failed to respond to 2 consecutive, adequate trials of non-clozapine antipsychotics. Remission of psychosis was defined as absence of overt psychotic symptoms for 6 months or more. The investigators classified the TRS as either early-onset or late-onset. Early onset TRS occurred when no remission occurred at any time whereas late-onset occurred when resistance developed after an interval of remission.

Of the original cohort, 246 or 87% had follow-up data. Four patients had died, and their mean age was significantly older than the cohort as a whole. In 33.7%, TRS had developed and their only distinguishing characteristic was a younger age of contact for treatment of psychosis: 25.2 years versus 27.9 years in the non-TRS group. Family history of psychosis, use of alcohol or cannabis, cognitive performance, and duration of untreated psychosis (DUP) did not differ between TRS and non-TRS groups. Those patients who were younger than 20 years at the time of first contact had an odds ratio of 2.49 for developing TRS, and men and Black people were also more likely to have TRS at follow-up.

About 70% of TRS patients had early-onset treatment resistance. Compared to the non-TRS group, those with early-onset TRS had a higher mean total PANSS score at baseline; 74% were male compared to 46% in the late-TRS group.

In the TRS cohort, about half the patients received clozapine, and they had on average a greater burden of total psychopathology and negative symptoms compared to the TRS patients who never received clozapine. The clozapine patients were also more likely to reside with family or friends.

According to the investigators, this is the largest first-episode cohort followed for onset of treatment resistance. They estimate that 23% of their patients had resistance to antipsychotic therapy from the onset of illness, and given the mean DUP of 4.5 weeks, which is quite brief, factors other than delayed treatment seem to be at play. If this study is generalizable, only a third of treatment resistance develops after the  onset of illness, and understanding that process could lead to prevention strategies. Furthermore, availability of biomarkers for TRS in early psychosis populations might help determine which patients would benefit from receiving clozapine immediately.

Lally J et al. Psychol Med. 2016;46(15):3231-3240. Abstract

Vitamin D deficiency in treatment-resistant schizophrenia

Vitamin D deficiency is associated with schizophrenia, although cause and effect are undetermined. Various published findings include low serum levels of vitamin D in people with chronic schizophrenia, elevated risk for schizophrenia in people who as neonates had low blood levels, and increased risk and higher symptom burden in early-psychosis cohorts (1). In a recent study from the Netherlands, whose population resides at latitudes similar to that of most Canadians, 28 people with treatment-resistant schizophrenia, 77% men and 61% Caucasian, who resided in a mental-health facility, underwent plasma vitamin D3 (calcidiol) analysis in April and June of the same year (2). A control group of 29 staff at the residence, mostly Caucasian women, also underwent testing. People using vitamin supplements were excluded. The researchers estimated the amount of time each participant spent outdoors daily was 2.3 hours for patients and 0.8 hour for staff.

The mean plasma level of vitamin D3 in April and June was significantly lower in the patients than in the staff, and the increase in plasma concentration during the spring was much less robust in the patients. The prevalence of vitamin D deficiency (as determined by plasma concentration) was 90% in April and 79% in June in the cohort of people with severe schizophrenia; in staff it was 17% in June. Because Caucasians have a greater capacity to synthesize vitamin D when their skin is exposed to sunlight, the investigators did subanalyses and found that non-Caucasian patients had lower mean plasma vitamin D than Caucasian patients, and the non-Caucasian patients’ mean plasma value did not increase during the spring.

The significance of these finding for the mental health of people with schizophrenia is unknown, and the researchers did not describe the medication treatments or the diet of the patients, other than to say it was healthy. Vitamin D is naturally available in eggs, some seafood, and is added to milk in some countries including Canada. The effects of vitamin D deficiency in general are most prominent on bone health. The central nervous system is however rich with vitamin D receptors, and deficiency has been linked to neuropsychiatric illness including depressive disorders and multiple sclerosis. Given that supplementation is recommended for Canadians, especially in the winter when it is impossible for most of us to obtain adequate vitamin D from sunlight, ensuring adequate intake for people with schizophrenia, in particular those in chronic care, is justifiable. The possibility that those with chronic illness cannot synthesize vitamin D with more-than-adequate sunlight exposure suggests that year-round oral supplementation is necessary to prevent or treat deficiency.


1. Chiang M, Natarajan R, Fan X. Vitamin D in schizophrenia. Evid Based Mental Health. 2016;19:6-9. Abstract

2. Bogers J, Bostoen T, Broekman TG. Low levels of vitamin D poorly responsive to daylight exposure in patients with therapy-resistant schizophrenia. Nordic J Psychiatry. 2016;70:262-266. Abstract

Refugees in Canada have a high incidence of psychosis

A recent article which I reviewed found evidence for an increasing incidence of schizophrenia in Canada. The researcher speculated that Canada’s high rate of immigration may contribute to this finding. Studies from other industrialized countries have found that immigrants, both in the first and second generation, have an elevated risk of developing schizophrenia, but evidence of this in Canada is lacking. A group from the Centre for Addictions and Mental Health in Toronto estimated the incidence of schizophrenia and schizoaffective disorder in Ontario, the most populous and immigrant-rich province of Canada, by examining hospital and billing records with the records maintained by Canadian immigration authorities.

The identified cohort was all Ontario residents who were age 14 to 40 years at the beginning of the 10-year period from 1999-2008. Because of the universal health-care system, all people who come to medical attention have their diagnosis recorded in a provincial data set. All those listed as an immigrants by the federal ministry of citizenship were classified as such whereas all those not listed were classified as non-immigrants. The investigators also noted which immigrants were admitted under refugee status, an indication of a more vulnerable and likely trauma-exposed group.

The rate of new-onset psychosis in the general population was 55.6 (95% CI 54.9–56.4) per 100 000 person-years and 51.7 (95% CI 49.2–54.4) per 100 000 person-years in first-generation immigrants; these rates are not significantly different. Among the immigrants classified as refugees, the rate was higher: 72.8 (95% CI 67.1– 78.9) per 100 000 person-years, but this is not significantly different from the other rates. Closer examination found that immigrants of various origins had differing rates; those from the Caribbean and Bermuda had significantly higher risk whereas those from northern and southern Europe and east Asia had significantly lower risk than the general population. Among refugees, those from east Africa and south Asia had significantly greater risk of psychosis than the general population.

The shortcomings of this kind of study are considerable, mainly the retrospective design and the reliance on administrative-level diagnostic data. Furthermore, the general population included second-generation immigrants who could not be identified by the study methods but who also probably have a higher risk of psychosis. Moreover, the researchers mention that refugees often have other mental illnesses such as posttraumatic stress disorder which may be misdiagnosed as psychosis. Despite these sources of bias, the findings support an emerging theoretical framework in which those immigrants most subject to discrimination, often because of their race, may be most vulnerable to onset of psychosis. Socioeconomic factors and trauma also likely play a role. Early intervention programs may increase their effectiveness by taking this into consideration. The findings also underline the significance of the federal role in health-care funding for refugees, a highly vulnerable population.

Anderson KK, Cheng J, Susser E, McKenzie KJ, Kurdyak P. Incidence of psychotic disorders among first-generation immigrants and refugees in Ontario. CMAJ. 2015;17:e279-e286. Article

Supersensitivity psychosis in treatment resistance

Guy Chouinard proposed the concept of dopamine supersensitivity psychosis (DSP) in 1978, a consequence of chronic antagonism of dopamine D-2 receptors which also is posited to cause tardive dyskinesia (1). The proposed mechanism is upregulation of D2 receptors in the basal ganglia, and tardive dyskinesia is itself considered one of the markers of the condition, also characterized by tolerance to increasing doses of antipsychotic. Supersensitivity psychosis patients may therefore represent a subtype of treatment resistance. In this study from Japan, the investigators examined this hypothesis in a group of patients with chronic psychosis (2).

The 147 patients enrolled had treatment-resistant schizophrenia or schizoaffective disorder as defined by failure of at least 2 antipsychotics at a dose equivalent to 600 mg chlorpromazine for 4 weeks. Although specifics of antipsychotic therapy were not provided, none of the patients was on clozapine. Their mean duration of illness was about 23 years. Supersensitivity was diagnosed if a patient met one of 3 criteria, which were adopted from Chouinard:

  • Antipsychotic tolerance indicated by relapse while on medication and failure to improve despite 20% or more increase in dosage
  • Rebound psychosis manifested by swift relapse with reduction or discontinuation of medication; the psychosis may involve new symptoms for a patient
  • Presence of tardive dyskinesia

The investigators found that 106 or 72.1% of the patients met at least one criterion for DSP; 56% had tolerance, 44% had tardive dyskinesia, and 42% had rebound psychosis. The patients were also classified by the presence or absence of deficit syndrome, defined by prominent negative symptoms assessed by standardized rating instruments. Of 55 patients judged to have deficit syndrome, the majority did not meet criteria for DSP; hence, DSP was significantly negatively associated with prominent deficit symptoms.

Although the researchers evaluated the present state of each subject, the main limitation of the study was reliance on chart reviews for the longitudinal course of patients’ illness. Furthermore, relapse of symptoms due to nonadherence could not be reliably distinguished from antipsychotic tolerance. The findings however suggest that supersensitivity psychosis may be an important contributor to treatment resistance, and that investigations using functional imaging and other techniques are warranted to validate the concept of DSP.

References Continue reading

Increasing prevalence of schizophrenia in Canada

The burden of schizophrenia for Canadian society is significant. In a review of incidence and prevalence studies published in peer-reviewed journals dating from 1953 through 2006, Dealberto estimated the one-year prevalence of schizophrenia in Canada at 2.5 to 5.6 per 1000. The investigator found that published incidence and prevalence rates have increased during the past 4 decades. Furthermore, the prevalence and incidence in Canada were greater than international median rates, with Canada’s estimated incidence rate situated between the 45th and 100th percentiles of international comparators.

Dealberto explained the relatively high prevalence of schizophrenia in Canada by three possible factors. First, many studies have found that immigrants have an increased incidence of schizophrenia in both the first and second generations. Canada has a high rate of immigration, about twice that of the United States; 20% of Canadians were born in another country. Second, schizophrenia is more common in countries at high latitude, although the cause of this effect is unknown. Third, urban populations have a greater prevalence of schizophrenia, and 80% of Canadians live in cities.

Population-based studies of the prevalence of treatment-resistant schizophrenia in Canada do not exist. Most reports indicate that treatment resistance occurs in about 30% of patients, hence based on Dealberto’s findings, the estimated one-year prevalence of treatment-resistant schizophrenia in Canada is 7.5 to 17 per 10,000.

Given these data, and assuming a continuation of current immigration policy in Canada, governments at federal and provincial levels must plan for and fund the health-care and social-service needs of a growing number of people with this disorder.


Dealberto MJ. Are the rates of schizophrenia unusually high in Canada? A comparison of Canadian and international data. Psychiatry Res. 2013;209(3):259-265. Abstract

Clozapine-induced seizures: prophylaxis or not?

Clozapine is associated with an elevated risk of seizures, especially with doses of 600 mg or greater. At such doses and with elevated serum levels, many psychiatrists consider adding a prophylactic antiepileptic, which was first recommended in the journal Neurology in 1991 (1). Caetano has reviewed available studies in an effort to determine if this is sound practice, and he concludes it is not (2). According to him, the risk of clozapine-induced seizures is greatest when the serum level is 1300 ng/ml or more, the equivalent of 4000 nmol/L. The evidence for this finding is skimpy, however, and consists of case reports: one from 1994, two from 1978, and one from 2001. To accurately determine the dose-response relationship between seizures and clozapine serum levels, prospective studies would be necessary.

Despite this shortcoming, Caetano’s recommendation against prophylaxis makes sense, at least if the serum level is not approaching 4000 nmol/L and the patient doesn’t have other risk factors such as coarse brain disease. The risk of pharmacokinetic interactions and additional adverse effects with anticonvulsants is high; for instance, phenytoin can decrease and lamotrigine can increase clozapine levels. He recommends other measures for managing seizure risk and what to do if a patient does have a seizure.


1. Devinsky O, Honigfeld G and Patin J. Clozapine-related seizures. Neurology. 1991;41:369–371. Abstract

2. Caetano D. Use of anticonvulsants as prophylaxis for seizures in patients on clozapine. Australas Psychiatry. 2014;22:78-82. Abstract

Did DSM-5 throw out the subtype baby with the bathwater?

Many clinicians have suspected and some evidence indicates that patients with the disorganized subtype of schizophrenia, or hebephrenia, do not respond as well to non-clozapine antipsychotics as do other subtypes. Investigators examined this hypothesis in 93 consecutively admitted schizophrenia patients at one hospital in Brazil. They confirmed the diagnosis with the Structured Clinical Interview for DSM-IV, and classified patients as either paranoid or disorganized subtype based upon the predominance of hallucinations and delusions versus disorganized speech and behavior using relevant PANSS items. Only 8 patients, who had either catatonic or residual schizophrenia, were excluded. Treatment resistance was defined as failure of two different antipsychotics, and these patients were offered either clozapine or “combination therapy.”

The mean age of the patients was about 32 years and 56% were male. The demographic profiles did not differ between the 25 disorganized and the 60 paranoid patients; however, the disorganized patients had significantly earlier age of onset, more severe symptoms, and lower functioning as measured by the Global Assessment of Functioning scale. Among the disorganized cohort, 60% were treatment-resistant compared with 20% of the paranoid cohort (p < 0.001). The clozapine response rate, as measured by at least 40% reduction in the total PANSS score, was greater than 60% in both groups. Although DSM-5 has eliminated subtypes of schizophrenia, this study suggests that the disorganized-paranoid axis may retain prognostic and hence diagnostic significance. Another interpretation is merely that positive symptoms respond better to non-clozapine antipsychotics than do disorganized features, which may respond better to clozapine. The study did not have masked raters and the total number of patients is small, so replication is necessary. The Brazilian researchers nonetheless advocate for clozapine use earlier in the course of treatment for disorganized-type patients. If this were adopted widely, clinical subtyping would likely require a more careful approach to evaluation than is carried out in usual practice, such as the use of standardized rating instruments. Reference Ortiz BB, Araújo Filho GM, Araripe Neto AG, Medeiros D, Bressan RA. Is disorganized schizophrenia a predictor of treatment resistance? Evidence from an observational study. Rev Bras Psiquiatr. 2013;35(4):432-434. Full text

The skeptical UK view of second-generation antipsychotics

Professor Tim Kendall, director of the National Collaborating Centre for Mental Health in the United Kingdom, gave a plenary lecture on “The Rise and Fall of the Atypical Antipsychotics” at the 7th Annual Pacific Psychopharmacology Conference on 20 September 2013, in Coquitlam, BC. According to Dr. Kendall, the National Institute for Health and Care Excellence (NICE), for which the National Collaborating Centre provides expertise in its psychiatric guideline development, concluded in a 2002 appraisal that the atypical antipsychotics might have greater efficacy and fewer adverse effects than typical antipsychotics. In 2009, NICE issued an updated guideline for schizophrenia treatment based on new evidence and multiple pairwise meta-analyses and found that the atypical or second-generation antipsychotics do not constitute a special class. In his view, the distinction is merely a marketing tool.

In selecting a medication, Dr. Kendall said we should ask our patients, “Would you rather be fat or stiff?” because the decision often comes down to whether patients can better tolerate extrapyramidal or metabolic adverse effects. An exception is clozapine, which falls into the “fat” category but remains the choice for treatment resistance; otherwise NICE does not recommend any specific antipsychotic over another.

A simultaneous economic analysis of antipsychotic treatment also produced provocative findings. Although the price of antipsychotic medications can vary widely, the model found no significant difference in cost effectiveness among the seven antipsychotics included in the analysis (amisulpride, aripiprazole, haloperidol, olanzapine, paliperidone, risperidone, zotepine). The driver of cost is relapse and hospitalization; drug-acquisition cost plays a minor role in the overall expense of a patient’s care. The lesson is that whatever medication a given patient is willing to take and can tolerate may improve adherence, reduce relapse, and save the immense price of inpatient treatment.

A Canadian cohort of patients with treatment-resistant schizophrenia

Researchers at the Centre for Addiction and Mental Health in Toronto characterized a cohort of people with schizophrenia who had enrolled in a genetics study. In this convenience sample of 478 subjects, 156 were considered treatment resistant (TR) according to American Psychiatric Association guidelines. The APA guidelines define treatment resistance as “little or no symptomatic response to multiple (at least two) antipsychotic trials of an adequate duration (at least 6 weeks) and dose (therapeutic range).”

The investigators found no correlation between treatment resistance and sex; family history of psychosis; schizophrenia subtype; cannabis, alcohol or drug use; or number of cigarettes consumed daily. However, the TR patients had been ill for a mean of 21 years compared with 15 years for the non-TR group (P < .001). Among patients identified as having white European ancestry, 37% were TR, whereas 18% of nonwhites were TR (P =.03). Several treatment factors were significantly correlated with treatment resistance. In the TR group, 33% were on clozapine compared with 13.3% in the non-TR group, and 25% of TR patients were on more than one antipsychotic, double the rate in the non TR group. Ten percent of the TR patients were on clozapine and at least one other antipsychotic. Furthermore, the TR patients had a mean of 3 failed medication trials, whereas the non-TR patients had a mean of 0.5 failed trials. This nonrandom sample is not necessarily representative of all TR patients, so the significance of the lower rate among non-white patients is unclear. The study corroborates previous research indicating that treatment resistance occurs in chronic patients, and that polypharmacy is used possibly at the expense of clozapine. References Teo C, Borlido C, Kennedy JL, De Luca V. The role of ethnicity in treatment refractory schizophrenia. Compr Psychiatry. 2013;54(2):167-172. Link to abstract.

Practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry. 2004;161(Suppl):1-56.