Another Strike Against Benzodiazepines

I just saw new data about the risk of benzodiazepines this time when used in polypharmacy with patients who have schizophrenia. The conclusion is that benzodiazepines added to other drugs may lead to higher mortality in this patient population [1].  This is yet another strike against benzodiazepines (see short link  Although antipsychotic polytherapy was not associated with higher mortality, antidepressant use was linked to lower mortality from suicide.

It’s still important to remember that the jury is still out on blanket recommendations supportive (or wholesale condemnation) of polypharmacy in general in patients with schizophrenia. [2-5]. It’s still best to remain skeptical and cautious about the practice.

1. Tiihonen, J., J. T. Suokas, et al. (2012). “Polypharmacy With Antipsychotics, Antidepressants, or Benzodiazepines and Mortality in Schizophrenia.” Arch Gen Psychiatry 69(5): 476-483.

Context Polypharmacy is widely used in the treatment of schizophrenia, although it is believed to have major adverse effects on the well-being of patients. Objective To investigate if the use of benzodiazepines, antidepressants, or multiple concomitant antipsychotics is associated with increased mortality among patients with schizophrenia. Design Registry-based case linkage study. Setting Academic research. Patients We linked national databases of mortality and medication prescriptions among a complete nationwide cohort of 2588 patients hospitalized in Finland for the first time with a diagnosis of schizophrenia between January 1, 2000, and December 31, 2007. Main Outcome Measures Hazard ratios (HRs) were computed for all-cause mortality during the use of antipsychotics, antidepressants, or benzodiazepines in outpatient care, adjusting for the effects of sociodemographic and clinical variables, geographic location, and current and past pharmacological treatments. Results Compared with antipsychotic monotherapy, concomitant use of 2 or more antipsychotics was not associated with increased mortality (HR, 0.86; 95% CI, 0.51-1.44). Similarly, antidepressant use was not associated with a higher risk for mortality (HR, 0.57; 95% CI, 0.28-1.16) and was associated with markedly decreased suicide deaths (HR, 0.15; 95% CI, 0.03-0.77). However, benzodiazepine use was associated with a substantial increase in mortality (HR, 1.91; 95% CI, 1.13-3.22), and this was attributable to suicidal deaths (HR, 3.83; 95% CI, 1.45-10.12) and to nonsuicidal deaths (HR, 1.60; 95% CI, 0.86-2.97). In total, 826 of 904 patients (91.4%) who used benzodiazepines had purchased prescriptions that contained more than 28 defined daily doses, violating treatment guidelines. Conclusions Benzodiazepine use was associated with a marked increase in mortality among patients with schizophrenia, whereas the use of an antidepressant or several concomitant antipsychotics was not. Antidepressant use was associated with decreased suicide deaths. The literature indicates that long-term use of benzodiazepines among patients with schizophrenia is more prevalent in other countries (eg, the United States) compared with Finland, which suggests that benzodiazepine use may contribute to mortality among this patient population worldwide.

2. Barnes, T. R. E. and C. Paton (2011). “Antipsychotic Polypharmacy in Schizophrenia: Benefits and Risks.” CNS Drugs 25(5): 383-399 310.2165/11587810-000000000-000000000.

Antipsychotic polypharmacy refers to the co-prescription of more than one antipsychotic drug for an individual patient. Surveys of prescribing in psychiatric services internationally have identified the relatively frequent and consistent use of combined antipsychotics, usually for people with established schizophrenia, with a prevalence of up to 50% in some clinical settings. A common reason for prescribing more than one antipsychotic is to gain a greater or more rapid therapeutic response than has been achieved with antipsychotic monotherapy. However, the evidence on the risks and benefits for such a strategy is equivocal, and not generally considered adequate to warrant a recommendation for its use in routine clinical practice in psychiatry. Combined antipsychotics are a major contributor to high-dose prescribing, associated with an increased adverse effect burden, and of limited value in helping to establish the optimum maintenance regimen for a patient. The relatively widespread use of antipsychotic polypharmacy identified in cross-sectional surveys reflects not only the addition of a second antipsychotic to boost therapeutic response, but also the use of as-required antipsychotic medication (mainly to treat disturbed behaviour), gradual cross-titration while switching from one antipsychotic to another, and augmentation of clozapine with a second antipsychotic where the illness has failed to respond adequately to an optimized trial of clozapine. This review addresses the clinical trial data and other evidence for each of these pharmacological approaches. Also reviewed are examples of systematic, practice-based interventions designed to reduce the prevalence of antipsychotic polypharmacy, most of which have met with only modest success. Guidelines generally agree that if combined antipsychotics are prescribed to treat refractory psychotic illness, this should be after other, evidence-based, pharmacological treatments such as clozapine have been exhausted. Further, their prescription for each patient should be in the context of an individual trial, with monitoring of the clinical response and adverse effects, and appropriate physical health monitoring.

3. Pandurangi, A. K. and A. Dalkilic (2008). “Polypharmacy with second-generation antipsychotics: a review of evidence.” J Psychiatr Pract 14(6): 345-367.

OBJECTIVE: The objective of this study was to review the prevalence of polypharmacy with second-generation antipsychotics (SGAs) in clinical practice, pharmacological reasons for such practice, and the evidence for and against such polypharmacy. METHODS: Clinical trial reports, case reports, and reviews were identified by a PubMed literature search from 1966 through October 2006, with retrieved publications queried for additional references. We excluded reports on augmentation with non-antipsychotic medications and polypharmacy involving combinations of SGAs and first-generation (conventional) antipsychotics (FGAs) or combinations of two FGAs. We identified 75 reports concerning SGA polypharmacy, from which we extracted data on study design, sample size, medications, rating scales, outcome, and conclusions. Data from randomized controlled trials and larger case series are presented in detail and case reports are briefly discussed. CONCLUSIONS: Polypharmacy with SGAs is not uncommon, with prevalence varying widely (3.9% to 50%) depending on setting and patient population, despite limited support from blinded, randomized, controlled trials or case reports that employed an A-B-A (monotherapy-combination therapy-monotherapy) design and adequate dosing and duration of treatment. Rather than prohibiting or discouraging co-prescription of SGAs, needs of patients and clinicians should be addressed through evidence-based algorithms. Based on unmet clinical needs and modest evidence from case reports, combinations of two SGAs may merit future investigation in efficacy trials involving patients with schizophrenia who have treatment-resistant illness (including partial response) or who are responsive to treatment but develop intolerable adverse effects. Other areas that may merit future research are efficacy of SGA polypharmacy for schizophrenia accompanied by comorbid conditions (eg, anxiety, suicidal or self-injurious behavior, aggression) and for reducing length of stay in acute care settings.

4. Tranulis, C., L. Skalli, et al. (2008). “Benefits and Risks of Antipsychotic Polypharmacy: An Evidence-Based Review of the Literature.” Drug Safety 31(1): 7-20.

Combination antipsychotic prescription is an increasingly common practice in clinical psychiatry. This clinical practice is at odds with clinical guidelines promoting antipsychotic monotherapy. Moreover, there has been increased concern over the safety profile of atypical antipsychotics in the last 10-15 years. We reviewed the literature on antipsychotic combinations with a focus on safety and efficacy. Multiple electronic database searches were complemented by relevant bibliography cross-checking and expert discussions. The review showed a literature that is dominated by case reports and uncontrolled studies. Polypharmacy was unequally studied, with some recent combinations (i.e. clozapine and risperidone) being extensively, albeit inconclusively, studied and other more commonly used combinations (first- with second-generation agents) receiving little attention. From an evidence-based perspective, further trials of antipsychotic association of sufficient power to address safety issues are needed before recommending any antipsychotic combination. Particular weaknesses of the present literature are low number of participants, lack of adequate control of confounding variables, short duration of experimental follow-up and inadequate monitoring of potential adverse effects. Copyright 2008 Adis Data Information BV

5. Zink, M., S. Englisch, et al. (2010). “Polypharmacy in schizophrenia.” Curr Opin Psychiatry 23(2): 103-111.

PURPOSE OF REVIEW: Although most guidelines recommend monotherapy in schizophrenia, the combined application of multiple psychotropic agents is very common, especially in treatment-refractory cases. We review the empirical basis supporting these attempts and their relevance for clinical practice. RECENT FINDINGS: Polypharmacy intends to address different aspects of treatment resistance, most importantly insufficient response of psychotic positive and negative symptoms, but also cognitive disturbances, affective comorbidity, obsessive-compulsive syndromes and side-effects of antipsychotic drugs. This review summarizes the current state of evidence of combined antipsychotic treatment strategies and the augmentation of antipsychotics with mood stabilizers, antidepressants and experimental substances. SUMMARY: In general, rigorous data on combination therapy in schizophrenia are rare and further randomized controlled trials, naturalistic trials and head-to-head-trials are necessary. Some evidence supports a combination of antipsychotics and antidepressants for negative symptoms and comorbid major depressive episodes. The add-on of lithium and mood stabilizers lacks compelling evidence, but might be beneficial for specific subgroups. For treatment-resistant cognitive symptoms, antipsychotic medication should be combined with cognitive remediation, as no pharmacological add-on strategy has gained convincing evidence so far. Treatment-emergent positive and/or negative symptoms under clozapine monotherapy might benefit from adding a second atypical substance.

%d bloggers like this: