Dr. Fidel Vila-Rodriguez, a BC Psychosis Program psychiatrist, received an American Psychiatric Foundation Early Academic Career Award on Schizophrenia Research at the APA Annual Meeting in New York in May, 2014. To learn about Dr. Vila’s research, visit his lab Web site NINET.CA.
Researchers from Australia have conducted the first controlled trial of estrogen in premenopausal women with treatment-resistant psychosis (1). They recruited 183 women with schizophrenia or schizoaffective disorder who were not pregnant, lactating, or postmenopausal; and who had no history of breast cancer, endocrine disorders, migraine with aura, or thromboembolism. Patients with acute mania were excluded. Patients were randomly assigned to receive either transdermal estradiol 100 mcg daily, transdermal estradiol 200 mcg daily, or placebo patch. The primary outcome measure during the 56-day trial was the Positive and Negative Syndrome Scale (PANSS). Other measures included the Montgomery-Asberg Depression Rating Scale (MADRS), the Repeatable Battery of Neuropsychological Status, adverse-effects monitoring, and serum estradiol concentration at the baseline and during treatment.
The baseline demographic, illness, and treatment characteristics did not differ among the placebo, 100 mcg-estradiol, and 200-mcg estradiol groups. Most subjects were outpatients, and the three groups had mean PANSS total scores of 72-75. Compared with the placebo group, both treatment groups had significant increases in serum estradiol concentration; and greater decreases in mean PANSS positive, general, and total scores. The effect size for positive symptoms, however, was 0.0 for the 100 mcg group and 0.44 for the 200 mcg group, which reflected a mean 3.3-point reduction in PANSS-positive score with the higher dose. No significant treatment effect was found for negative symptoms or cognition. The only significant adverse effect was an increase of irregular menses in the 200 mcg group compared with the placebo group.
The investigators acknowledge that this trial was short-term and that the risks of thromboembolism and endometrial carcinoma may accumulate during longer-duration therapy. Raloxifene, a selective estrogen receptor modulator, entails a lower risk of these adverse effects. In 2011, investigators from Spain reported on a randomized trial of 16 postmenopausal women who had significant mean reduction of positive, negative, and general symptoms compared with a comparable placebo group (2). Case reports exist of raloxifene use in premenopausal women with treatment-resistant schizophrenia (3,4), but controlled trials in this population have not been published.
1. Kulkarni J, Gavrilidis E, Wang W. Estradiol for treatment-resistant schizophrenia: a large-scale randomized-controlled trial in women of child-bearing age. Molecular Psychiatry. Published online 15 Apr 2014. Abstract
2. Usall J, Huerta-Ramos E, et al. Raloxifene as an adjunctive treatment for postmenopausal women with schizophrenia: a double-blind, randomized, placebo-controlled trial. J Clin Psychiatry. 2011;72(11):1552-1557. Abstract
3. Raveendranathan D, Shivakumar V, Jayaram N, Rao NP, Venkatasubramanian G. Beneficial effects of add-on raloxifene in schizophrenia. Arch Womens Ment Health. 2012;15(2):147-148. Abstract
4. Shivakumar V, Venkatasubramanian G. Successful use of adjuvant raloxifene treatment in clozapine-resistant schizophrenia. Indian J Psychiatry. 2012;54(4):394. Full text
A team of BC psychologists has performed the first meta-analysis of cognitive-behavioral therapy for medication-resistant psychosis. The 16 published studies that met their inclusion criteria comprised 12 trials and 639 individual patients. Medication resistance was defined as inadequate response of positive symptoms to at least one medication at adequate dose and duration, or treatment with clozapine. All the trials entailed assignment to either individual CBT for 10 to 24 sessions, or to a control intervention such as treatment as usual, psychoeducation or befriending. Four trials lacked masked raters. Outcome measures were typically PANSS or BPRS, and most studies had a follow-up assessment 3 to 18 months after completion of treatment. Based on pooled outcome data, effect size was derived with Hedge’s g.
For improving positive symptoms, the effect size of CBT compared to control intervention at the end of treatment was 0.47. At follow-up 3-18 months after treatment, the effect size was 0.41. Among studies with an outcome measurement for general psychopathology, such as depression and anxiety, the effect sizes were 0.52 at treatment end and 0.40 at follow-up. According to the researchers, excluding studies without masked raters did not significantly change the effect sizes.
This meta-analysis yielded a medium effect size for time-limited CBT in medication-treated patients with residual positive symptoms. The results suggest improvement may be maintained beyond a year. These were not necessarily treatment-resistant patients as typically defined, although some were on clozapine. Research on other important outcomes such as hospital admission, psychosocial functioning, and suicide would help determine the place of CBT in managing treatment-resistant psychosis.
Burns AM, Erickson DH, Brenner CA. Cognitive-behavioral therapy for medication-resistant psychosis: a meta-analytic review. Psychiatr Serv. Published online 1 Apr 2014. Abstract
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
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.
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
In what they call the largest study to date of clozapine discontinuation, researchers examined a Veterans Administration cohort in the United States of 320 patients with schizophrenia or schizoaffective disorder, 91% male, who received clozapine. The Brief Psychiatric Rating Scale (BPRS) was used to assess symptoms. During 15 years of follow-up, 57% of patients had at least one discontinuation, which occurred most often between 3 and 6 months after treatment initiation.
Factors associated with an elevated likelihood of discontinuation were:
• African-American race
• Older age
• Lower disability award from the VA
• Smaller reduction in BPRS score
The top three causes of discontinuation were nonadherence (35%), adverse effects (28%), and administrative reasons (19%). The adverse effects related to discontinuation in order of frequency were:
• Hematologic, most often neutropenia
• Nervous system including sedation and seizures
• Cardiovascular including hypotension and tachycardia
• Autonomic including sialorrhea
• Weight gain
Agranulocytosis occurred in 3 patients, whereas lesser cases of granulocytopenia which still eliminated the possibility of rechallenge occurred in 4 patients; 3.3% of discontinuations therefore precluded restarting clozapine. One patient died of agranulocytosis; the only other clozapine-related death was in a patient with adynamic bowel and consequent aspiration.
The investigators looked at outcomes following discontinuation. Among 183 patients who stopped clozapine, only 16% restarted it and about half of those continued it. Among the approximately 170 patients who remained off clozapine and who received at least 3 months treatment with another antipsychotic, the mean BPRS score rose significantly from 39 to 52.
The limitations of the study include its naturalistic design and retrospective method.
The data confirm clinical impression that clozapine trials often do not succeed, and the chief challenges are managing adherence and adverse effects. Patients who can’t tolerate clozapine do poorly. We need more options for treatment-resistant psychosis.
Davis MC, Fuller MA, Strauss ME, Konicki PE, Jaskiw GE. Discontinuation of clozapine: a 15-year naturalistic retrospective study of 320 patients. Acta Psychiatr Scand. Published online 2 Dec 2013. Abstract
A study from the UK examined 67 cases of neuroleptic malignant syndrome and 254 controls (1). The researchers made several interesting findings, in particular that patients on 3 or more antipsychotics had an odds ratio of 5.4 for NMS. This, along with evidence for increased risk of diabetes in patients on multiple antipsychotics (2), give reason to be cautious about antipsychotic polypharmacy.
1. Retrospective chart review on exposure to psychotropic medications associated with neuroleptic malignant syndrome. Su Y-P, Chang C-K, Hayes RD, et al. Acta Psychiatr Scand. Published online 15 November 2013. Abstract
2. Treatment with antipsychotics and the risk of diabetes in clinical practice. Kessing LV, Thomsen AF, Mogensen UB, Andersen PK. Br J Psychiatry. 2010;197:266–271. Full text
In this systematic review, the investigators sought to find the cost of treatment-resistant schizophrenia and schizoaffective disorder in the United States, which they estimate affects 500,000 people (1). They defined treatment resistance as failure to respond to one or more adequate antipsychotic trials, which is more inclusive than most clinical definitions. They examined studies published from 1996 through 2011 and included 65 that met their criteria. In addition to demographics and illness characteristics of the study populations, they looked at psychiatric and medical comorbidities, employment, and mortality including suicide. They also attempted to obtain data on treatment costs, productivity losses, and impacts on quality of life.
The rate of treatment response in clinical trials among TRS patients ranged from 14% to 25%. Compared with the general population, the TRS population had on average higher rates of substance use including tobacco addiction, of aggressive behavior, and a high burden of adverse medication effects. Suicidal ideation or behavior occurred in 54% of patients.
The standard metric for burden of disease in a population is quality-adjusted or disability-adjusted life-years (QALYs or DALYs), which include impacts on longevity and quality of life, but the investigators found no studies that calculated these for TRS or TRSA. One study provided health utility weights, which estimate the impact of a disease on a scale in which 0 is equal to death and 1 is equal to perfect health. Severe schizophrenia was given a weight of 0.56, similar to that of people on chronic renal dialysis; based on this, the investigators estimated a loss of 145,000 QALYs per year.
Estimates of total health-care costs of TRS were $66,360 to $163,795 per patient-year in 2012. This compares with an estimate of about $15,500 to $22,300 for non-treatment-resistant patients. In TRS and non-TRS, about half these costs were attributable to inpatient treatment. The authors estimated that the 20% of patients with TRS account for up to 80% of all schizophrenia health-care costs. No studies looked at lost productivity, but unemployment likely exceeds 70% in TRS patients, and costs related to crime, incarceration, and care-giver impacts were also lacking.
The limitations of the study are mostly related to deficiencies in the body of publications on the societal and personal impacts of this disorder. Given these gaps in data, the researchers believe that their findings represent an underestimate of the costs of TRS. This illness is costly on many levels, some of which have not been adequately studied and others of which may not be quantifiable.
1. Kennedy JL, Altar CA, Taylor DL, Degtiar I, Hornberger JC. The social and economic burden of treatment-resistant schizophrenia: a systematic literature review. Int Clin Psychopharmacol. Published online 29 Aug 2013. Abstract
The inflammatory hypothesis of schizophrenia is getting more attention recently along with research on the role of anti-inflammatory medications. A European group has published a meta-analysis of 26 randomized controlled trials that fulfilled their inclusion criteria testing the following agents with anti-inflammatory properties (1):
• omega-3 fatty acids
• N-acetylcysteine (NAC)
The investigators calculated Hedge’s g to derive an effect size for reduction of psychotic symptom severity; results were significant for aspirin (ES=0.3), estrogens (ES=0.51), and NAC (ES=0.45). Two trials used aspirin at 1000 mg daily in combination with antipsychotic medication for 3-4 months. The estrogen trials involved mostly women subjects and used a wide range of doses for antipsychotic augmentation. The NAC findings are based on only one trial. Most of the studies did not involve subjects clearly defined as treatment-resistant, but until more evidence is available, the findings may be helpful in select treatment-resistant patients.
1. Sommer IE, Van Westrhenen R, Begemann M, et al. Efficacy of anti-inflammatory agents to improve symptoms in patients with schizophrenia: an update. Schizophr Bull. 2013 doi: 10.1093/schbul/sbt139 (published online October 8, 2013) Abstract
The latest trial for clozapine-resistant patients comes from Italy (1). The Clozapine Haloperidol Aripiprazole Trial (CHAT) is a multicentre, randomized, 12-month trial of patients with schizophrenia and persistent positive symptoms despite at least six months of clozapine therapy at a minimum dose of 400 mg. Outcome measures included the Brief Psychiatric Rating Scale and, for subjective rating of adverse effects, the Liverpool University Neuroleptic Side Effect Rating Scale (LUNSERS). The primary outcome was treatment discontinuation, “a pragmatic and reliable estimate of treatment efficacy and tolerability” according to the authors.
Based on a power calculation, the investigators intended to recruit 194 participants but randomized 106 patients, about 65% men and with a mean age of 41 years. In addition to clozapine, patients received either haloperidol or aripirpazole for 12-months. Baseline demographics and BPRS scores did not significantly differ between the groups. The dose of adjunctive antipsychotic was adjusted according to clinical response, and the patients could receive any necessary additional medications including mood stabilizers and antidepressants. Although the investigators did not report the mean dose of adjunctive antipsychotics in this publication, they reported in 2011 that at month 3, the mean aripiprazole dose was 11.8 mg and the mean haloperidol dose was 2.8 mg (2).
During the study, 19 aripirpazole and 15 haloperidol patients withdrew, which was not significantly different. At 6 months, the mean BPRS score in the aripirpazole group had decreased by 8.8, and in the haloperidol group, by 8.1; the improvement persisted at 12 months. By 3 months the mean LUNERS score decreased significantly in the aripirpazole group but not in the haloperidol group, which indicated that patients taking aripirpazole reported a decrease in adverse effects whereas those taking haloperidol did not.
Both aripirpazole and haloperidol showed effectiveness in augmenting clozapine, but aripirpazole was better tolerated by self-report. Despite this apparent preference for aripirpazole, the groups had a comparable rate of treatment discontinuation: about a third of patients dropped out, most during the first 6 months of augmentation. The findings of the study are limited by lack of statistical power and of a placebo arm. The researchers claim, however, that CHAT is the longest non-industry-sponsored RCT of treatment-resistant schizophrenia.
1. Cipriani A, Accordini S, Nose M, et al. Aripiprazole versus haloperidol in combination with clozapine for treatment-resistant schizophrenia. J Clin Psychopharmacol. 2013;33: 533-537. Abstract
2. Barbui C, Accordini S, Nose M, et al. Aripiprazole versus haloperidol in combination with clozapine for treatment-resistant schizophrenia in routine clinical care: a randomized, controlled trial. J Clin Psychopharmacol. 2011;31: 266-273. Abstract