We just published a report in the Journal of Clinical Psychopharmacology of a woman who abused dimenhydrinate for years. Only after she had sustained abstinence from this over-the-counter remedy for nausea did her psychosis respond well to treatment. Read the case report.
In 1937, Cerletti conceived electroconvulsive therapy (ECT) as a treatment for schizophrenia, a safer way than injecting a drug to induce seizures, which by a still-unknown mechanism has an antipsychotic effect. For patients who are acutely suicidal or catatonic, ECT is often life-saving, but for chronic schizophrenia, it is overlooked as a treatment option perhaps because of lingering stigma. The combination of ECT and antipsychotics including clozapine is reported to be safe, but controlled trials of ECT are rare.
A team from New York has published the first single-blind trial of clozapine and ECT. Patients with DSM-IV schizophrenia who had failed to respond to 12 weeks of clozapine therapy despite adequate serum levels were randomly assigned to either continue clozapine alone or to a course of bilateral ECT under general anesthesia, 3 times weekly for 4 weeks, then twice weekly for 4 more weeks. The patients who continued clozapine but remained unwell after 8 weeks were given a course of ECT with the same parameters. In both treatment groups, the dose of clozapine on which the patient entered the study remained unchanged. Patients with significant depression or non-nicotine substance-use disorder were excluded.
The outcome measures, performed by masked raters at outset and weekly, were the Brief Psychiatric Rating Scale (BPRS) and the Clinical Global Impression-Severity scale (CGI). Patients also underwent a neuropsychologic battery at baseline and at treatment completion. Response was defined as a 40% or greater improvement in the psychotic subscale of the BPRS and a CGI of 3 (mildly ill) or less. The investigators note that these are stringent response criteria.
The ECT group comprised 20 patients of whom 17 completed the 8-week course; the clozapine-only group comprised 19 patients of whom 16 completed the trial. Ten of the patients receiving clozapine and ECT met response criteria whereas none of the clozapine-only patients did. In the crossover phase, 9 of 19, or 47% of the patients responded to the combined treatment.
The cognitive evaluations showed reduction in mean speed of processing in the ECT-treated group, whereas executive function and episodic memory showed inconsistent effects across patients. The collective global neurocognitive values did not change significantly in either group. As for other adverse effects, no patients had spontaneous seizures, but 2 ECT patients had transient confusion.
At the BC Psychosis Program, we frequently offer ECT to patients who have not had adequate response to other treatments. This study provides high-quality evidence that clozapine-resistant patients can benefit from this approach, and cognitive impairment, while not absent, is typically quite mild.
Petrides G, Malur C, Braga RJ et al. Electroconvulsive therapy augmentation in clozapine-resistant schizophrenia: A prospective, randomized study. Am J Psychiatry. Published online Aug 26, 2014. Abstract
Dr. Ric Procyshyn, a UBC pharmacologist and researcher, is the principal investigator in two research projects underway at BC Psychosis Program. The goal is to recruit 50 patients for each study, and participants must give voluntary informed consent.
The first study, titled A Pilot Study to Determine if Pantoprazole Modifies Steady-State Plasma Concentrations of Orally Administered Psychotropic Medications, will look at the effects of proton pump inhibitors (PPIs) on the absorption and blood levels of psychiatric medications. People who smoke, are overweight, or take clozapine are prone to gastroesophageal reflux disease (GERD), hence many people with schizophrenia end up receiving PPIs. Patients at BC Psychosis Program with gastric reflux who would benefit from treatment, and who are taking valproic acid, lithium, or a second-generation antipsychotic, will receive the PPI pantoprazole for nine days. During this time, plasma concentrations of the medications as well as gastrin, a digestive hormone, will be obtained. If the medication benefits a patient, treatment can continue.
The second project is A Pilot Study to Determine How Frequency of Administration Modifies Steady-State Plasma Concentrations of Orally Administered Clozapine. Patients on clozapine often receive it once every 24 hours, usually at bedtime because of its sedating properties. However, clozapine has a short half-life and dissociates quickly from the dopamine D2 receptor, so it may work better with more frequent dosing. Patients already on clozapine will be assigned to receive it once or twice a day for 15 days during which plasma concentration of clozapine will be monitored along with effects on glucose, body weight, and symptoms of psychosis.
In a randomized, controlled trial published in 2014, intravenous sodium nitroprusside was shown to be effective in further reducing positive and negative symptoms of schizophrenia in patients taking a number of antipsychotics including chlorpromazine, haloperidol, olanzapine, risperidone and quetiapine. The same researchers based in Brazil and Canada have published two case reports of patients on clozapine who safely received intravenous sodium nitroprusside (1). The patients, both men, were 22 and 33 years old, and they had persistent positive symptoms of psychosis despite receiving clozapine at adequate dose and duration. Serum clozapine levels were not reported.
The men received nitroprusside according to the same protocol published in JAMA Psychiatry: an infusion of 0.5 microgram per kilogram per minute for four hours. In both cases, the improvements in positive and negative symptoms as measured by the Positive and Negative Syndrome Scale became apparent within hours and lasted for days.
The report does not mention cardiovascular parameters, but in a personal communication, the investigators said that at this dose, nitroprusside has little effect on blood pressure in normotensive people despite treatment with antipsychotics that can reduce blood pressure. The two patients did not receive further infusions because of concern about toxicity with repeated doses of nitrous prusside, which transiently produces small amounts cyanide; however, toxicity is rare with doses less than 5 micrograms per kilogram per minute. With infusions lasting more than 24 hours or in patients with renal insufficiency, accumulation of thiocyanate may occur, which can cause delirium (2). The risk of such toxic events appears to be minimal in low-dose nitroprusside treatment in appropriately selected patients.
This treatment has promise for clozapine-resistant schizophrenia, a severe disease with no well-established treatments except possibly electroconvulsive therapy (ECT). Randomized controlled trial in clozapine-resistant schizophrenia, also called ultra-resistant or super-refractory schizophrenia, are warranted.
1. Maia-de-Oliveira JP, Belmonte-de-Abreu P, Bressan RA, Cachoeira C, Baker GB, Dursun SM, Hallak JE. Sodium nitroprusside treatment of clozapine-refractory schizophrenia. J Clin Psychopharmacol. 2014;34:761-763.
2. Michel T, Hoffman BB. Treatment of myocardial ischemia and hypertension. In: Brunton L, Chabner B, Knollman B, eds. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 12th ed. New York, NY: McGraw-Hill Co., 2011 (online version).
In 2013, Drs. Jaime Hallak, Joao Paulo Maia-de-Oliveira and associates in Ribeirao Preto, Brazil, published results from a randomized controlled trial of intravenous nitroprusside in schizophrenia. Two Canadian researchers from the University of Alberta collaborated on the trial. This study was the first to find that sodium nitroprusside, a treatment for hypertensive crises, has a rapid and prolonged effect on both positive and negative symptoms in patients with acute psychosis. The presumed mechanism is enhancement of nitric oxide in the central nervous system, which may modulate the NMDA receptor-cGMP pathway. In normotensive patients, nitroprusside has minimal effect on blood pressure, and cyanide accumulation is a theoretical concern but occurs only after 72 hours or more of continuous infusion. In treating schizophrenia, the infusion dose is 0.5 mg/kg/minute for four hours.
In the initial trial published in JAMA Psychiatry, Hallak’s team used the Brief Psychiatric Rating Scale and the negative subscale of the Positive and Negative Syndrome Scale (PANSS) as outcome measures. A significant effect on certain components occurred within the first two to three hours of treatment, and improvement endured for four weeks. All the patients were also receiving an antipsychotic other than clozapine.
I met with Jaime, Joao Paulo and their team at the University of Sao Paulo Hospital in Ribeirao Preto and was able to observe a treatment. When I first met the patient, whose infusion had begun 10 minutes before, she appeared anxious and tended to avoid eye contact. When I returned 90 minutes later, she was engaged in an art activity and was eager to show me what she had created. She smiled broadly and even tested her English vocabulary a little. The researchers said that they often see an improvement in the patients’ affect over the course of the infusion, and they are trying to find ways to measure this more objectively. Although data are still limited, the effect in treatment-resistant patients tends to be more delayed.
Further studies of nitrous prusside in Ribeiroa Preto are underway, including for treatment-resistant patients, some on clozapine, and on neurophysiologic effects as detected with fMRI and event-related potential. Because the benefits of the treatment begin to wane after four weeks, they are planning a controlled trial of weekly nitrous prusside infusions for four weeks followed by 60 days of observation.
Hallak JEC, Maia-de-Oliveira JP, Abroa J, et al. Rapid Improvement of Acute Schizophrenia Symptoms After Intravenous Sodium Nitroprusside: A Randomized, Double-blind, Placebo-Controlled Trial. JAMA Psychiatry. 2013;70:668-676. Abstract
Photo: Left to right: Dr. Jaime Hallak, Dr. Joao Paolo Maia-de-Oliveira, Juliana Almeida (audiologist), their patient and her mother
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
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. 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
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