Treatment-refractory Psychosis Research Articles

“God speaks to me through a dove”. The evidence of clozapine in treatment-refractory psychosis

IntroductionClozapine is an atypical antipsychotic synthesised in 1958. It was withdrawn from the market in the 1970s due to the appearance of agranulocytosis, but was reintroduced due to strong evidence of its efficacy and superiority over other antipsychotics in treatment-resistant schizophrenia.ObjectivesTo describe the adequate response to clozapine in treatment-refractory psychosis.MethodsReview of the scientific literature based on a relevant clinical case.ResultsA 16-year-old woman was admitted to a psychiatric inpatient unit for psychotic symptoms and behavioural disorders. She lives with her father and older sister; she has not been in contact with her mother, who lives in another country, for several years. She attends secondary school, with poor academic performance. Maternal diagnosis of schizophrenia. She started using cannabis two years ago, with a progressive increase up to 20 grams per week. He reports the onset of a feeling of strangeness a year ago, with progressive isolation in his room, referring to delirious ideation of harm towards classmates and people from his town, self-referentiality and delirious interpretations of religious mystical content (“God speaks to me through a dove”). He comments on the phenomenon of theft and thought-reading. Soliloquies and unmotivated laughter are observed.ConclusionsTreatment was started with risperidone, progressively increasing the dose up to optimisation, without achieving a decrease in positive symptoms, but with the appearance of excessive sedation and sialorrhoea. It was combined with aripiprazole up to 20mg, maintained for a couple of weeks, without significant clinical improvement. Given the failure of two lines of therapy, it was decided to change to clozapine up to a dose of 75mg, with adequate tolerance and response, achieving a distancing of the delirious ideation. Regular haematological controls were performed, with no alterations in haemogram or troponins.Disclosure of InterestNone Declared

Longitudinal changes in brain metabolites in healthy controls and patients with first episode psychosis: a 7-Tesla MRS study.

Seven Tesla magnetic resonance spectroscopy (7T MRS) offers a precise measurement of metabolic levels in the human brain via a non-invasive approach. Studying longitudinal changes in brain metabolites could help evaluate the characteristics of disease over time. This approach may also shed light on how the age of study participants and duration of illness may influence these metabolites. This study used 7T MRS to investigate longitudinal patterns of brain metabolites in young adulthood in both healthy controls and patients. A four-year longitudinal cohort with 38 patients with first episode psychosis (onset within 2 years) and 48 healthy controls was used to examine 10 brain metabolites in 5 brain regions associated with the pathophysiology of psychosis in a comprehensive manner. Both patients and controls were found to have significant longitudinal reductions in glutamate in the anterior cingulate cortex (ACC). Only patients were found to have a significant decrease over time in γ-aminobutyric acid, N-acetyl aspartate, myo-inositol, total choline, and total creatine in the ACC. Together we highlight the ACC with dynamic changes in several metabolites in early-stage psychosis, in contrast to the other 4 brain regions that also are known to play roles in psychosis. Meanwhile, glutathione was uniquely found to have a near zero annual percentage change in both patients and controls in all 5 brain regions during a four-year follow-up in young adulthood. Given that a reduction of the glutathione in the ACC has been reported as a feature of treatment-refractory psychosis, this observation further supports the potential of glutathione as a biomarker for this subset of patients with psychosis.

High-Dose Therapy in Treatment-Refractory Psychosis: A Retrospective Study.

Objective: To examine the impact of antipsychotic dose adjustments (mainly reduction) on the efficacy and tolerability of antipsychotic medications (APMs) to facilitate hospital discharge in long-term hospitalized forensic patients with treatment-refractory psychosis. Methods: This was a retrospective review of the medical charts of 22 patients with psychosis who were discharged from January 2020 to August 2020 from a long-term state psychiatric facility after restoration of their competency to stand trial. Due to the lack of specific guidelines, the high-dose therapy was defined as a dose ≥ 50% above the average package insert dose. The primary outcome was discharge time after the antipsychotic dosing adjustments. Results: Sixty-eight percent of subjects, who were hospitalized for a mean ± SD total of 11.6 ± 5.3 months, were discharged after 2.3 ± 0.78 months of 44.4% antipsychotic dose reduction. Two patients, who were hospitalized for 14.5 ± 6.7 months, were discharged after 4 months of optimizing their subtherapeutic doses. Five patients, who were already receiving effective dosages, were discharged after a total hospital duration of 6.8 ± 2.17 months. Conclusions: The results from this study extend the finding of beneficial effects of antipsychotic dose reduction from prior reports to the forensic population.

55.3 Clozapine: Practical Applications for the Child and Adolescent Psychiatrist

Clozapine is widely accepted as an effective treatment option for treatment-refractory schizophrenia and schizoaffective disorder. However, minimal literature exists for the use of clozapine in the pediatric population. In cases of early-onset psychosis, it is important that prescribers appropriately utilize clozapine when treating youth with treatment-refractory psychosis.

Impact of medications, mood state, and electrode placement on ECT outcomes in treatment-refractory psychosis

BackgroundTreatment-refractory psychosis (TRP) is a significant clinical challenge. While clozapine is frequently effective, alternate or augmentation strategies are often necessary. Evidence supports effectiveness of electroconvulsive therapy (ECT), but questions remain about optimal treatment parameters and impacts of concomitant pharmacotherapy. Objective/Hypothesis: To analyze the impact of clozapine, anticonvulsant medication, mood state, and ECT electrode placement on outcomes in TRP. We hypothesized that ECT would lead to greater reduction in positive symptoms, particularly in patients receiving clozapine. MethodsRetrospective study in a tertiary TRP program. The Positive and Negative Syndrome Scale (PANSS) was used for clinical outcomes, with positive subscore as primary outcome. Clinical and ECT data were analyzed using a linear modelling approach, controlling for relevant covariates. ResultsA total of 309 patients were included. ECT plus clozapine associated with greater improvement in positive, general, and total symptoms than ECT alone. ECT associated with greater improvement in negative symptoms in depressed patients. Bifrontal placement was mostly equivalent to bitemporal, with greater reduction of positive symptoms in patients receiving clozapine, and associated with lower electrical dose in patients on anticonvulsants. Clozapine increased seizure duration, while anticonvulsants decreased it. Anticonvulsant use in ECT patients associated with equivalent to slightly improved symptom reduction. ConclusionsECT's benefit in TRP may be greatest in patients receiving clozapine. ECT can improve negative symptoms in depressed TRP patients. Bifrontal placement is effective in TRP. Clozapine and anticonvulsants have opposite effects on seizure duration, but anticonvulsants may not adversely affect clinical outcomes of ECT for TRP.

Antipsychotic-induced supersensitivity – A reappraisal

Tardive dyskinesia, psychotic relapse and treatment-refractory psychosis have long been associated. A common underlying mechanism involving antipsychotic-induced 'supersensitivity', albeit in different brain pathways, was proposed as early as 1978. This piece seeks to reappraise the concept and potential implications of antipsychotic-induced supersensitivity. Evidence increasingly suggests that chronic antipsychotic exposure induces neuroadaptive physiological changes in dopaminergic, and other, neurotransmitter systems that may render some individuals more vulnerable to psychotic relapse - including those receiving continuous antipsychotic treatment. It is possible that in treating every episode of psychosis with prolonged or indefinite antipsychotic therapy, we paradoxically increase the risk of psychotic relapse in a significant proportion of people. A greater appreciation of supersensitivity may allow us to optimise any potential benefits of antipsychotics while minimising the risk of inadvertent iatrogenic harms. More research is needed to improve our understanding of the underlying neurophysiology of supersensitivity and to better identify which individuals are most vulnerable to its development. It is time we paid more attention to the concept, emerging evidence and potential implications of antipsychotic-induced supersensitivity and, where appropriate, adjusted our practice accordingly.

Facial mask masking tardive dyskinesia

IntroductionFacial covering and mask use is generally considered a preventive measure in reducing spread of infectious respiratory illnesses. With the COVID-19 pandemic, covering of the face, except the eyes, has become the norm for the first time for most people. Social interactions and clinical observation rely heavily on non-verbal communication of which facial expression is of utmost importance. While clinicians, especially in mental health settings, are acutely aware of the loss of information transmitted through the lower half of the face, signs of tardive dyskinesia may be forgotten in the list of potentially missed information.ObjectivesTo reflect on possible failure to detect orobuccolingual movements of tardive dyskinesia due to use of facial masks.MethodsReflection on a clinical case of a patient with a treatment refractory psychosis who presents to an outpatient appointment with a facial mask. After the appointment, a family member transmitted having observed what appeared to be involuntary masticatory movements in the patient.ResultsFacial masks and coverings occult signs that may be visible on the lower half of the face.ConclusionsFacial masks and coverings are essential in preventing COVID-19 contagion. Clinicians must keep in mind loss of information when part of the face is not visible. Tardive dyskinesia with orobuccolingual movements may be missed behind a mask. Family or other people who cohabit with the patient are essential information providers.

Outcomes in treatment-resistant schizophrenia: symptoms, function and clozapine plasma concentrations.

Background:Clozapine is the only medication licenced for treating patients with treatment-refractory schizophrenia. However, there are no evidence-based guidelines as to the optimal plasma level of clozapine to aim for, and their association with clinical and functional outcome.Objective:We assessed the relationship between clinical and functional outcome measures and blood concentrations of clozapine among patients with treatment-refractory psychosis.Methods:Data were reviewed in 82 patients with treatment-refractory psychosis admitted to a specialised tertiary-level service and treated with clozapine. Analysis focussed on the relationship between clozapine and norclozapine plasma concentrations and the patient’s clinical symptoms and functional status.Results:Clinical symptom improvement was positively correlated with norclozapine plasma concentrations and inversely correlated with clozapine to norclozapine plasma concentrations ratio. Clozapine concentrations showed a bimodal association with clinical improvement (peaks around 350 and 660 ng/ml). Clinical symptom improvement correlated with functional outcomes, although there was no significant correlation between the latter and clozapine or norclozapine plasma concentrations.Conclusion:Clozapine treatment was associated with optimal clinical improvement at two different peak plasma concentrations around 350 and 650 ng/ml. Clinical improvement was associated with functional outcome; however, functionality was not directly associated with clozapine concentrations. A subset of patients may require higher clozapine plasma concentrations to achieve clinical improvement.

On Neuropsychiatric Manifestations of Basal Ganglia Injury: A Report of Three Cases and Literature Review

The basal ganglia have been considered to primarily play a role in motor processing. A growing body of theoretical and clinical evidence shows that in addition to the motor functions the basal ganglia play a key role in perceptual and visual disturbances. This role may be evident in patients with basal ganglia pathology and subsequent manifestation of symptoms that include cognitive, perceptual, and affective disturbances. We present three cases with basal ganglia pathology that demonstrate affective and psychotic symptoms. Two of the cases presented with late onset psychotic disturbances suggesting likely neurological etiologies. The third case presented with treatment refractory psychosis and symptoms that are rare for a diagnosis of schizophrenia. The role of incidental bilateral basal ganglia calcifications in all the cases is discussed. A review of current literature highlighting various neuropsychiatric manifestations of basal ganglia pathologies in various patients with psychiatric symptoms is presented.

Translational Significance of Selective Estrogen Receptor Modulators in Psychiatric Disorders.

Accumulating data from various clinical trial studies suggests that adjuvant therapy with ovarian hormones (estrogens) could be effective in reducing cognitive deficit and psychopathological symptoms in women with psychiatric disorders. However, estrogen therapy poses serious limitations and health issues including feminization in men and increased risks of thromboembolism, hot flashes, breast hyperplasia, and endometrium hyperplasia when used for longer duration in older women (aged ≥ 60 years) or in women who have genetic predispositions. On the other hand, selective estrogen receptor modulators (SERMs), which may (or may not) carry some risks of hot flashes, thromboembolism, breast hyperplasia, and endometrial hyperplasia, are generally devoid of feminization effect. In clinical trial studies, adjuvant therapy with tamoxifen, a triphenylethylene class of SERM, has been found to reduce the frequency of manic episodes in patients with bipolar disorder, whereas addition of raloxifene, a benzothiophene class of SERM, to regular doses of antipsychotic drugs has been found to reduce cognitive deficit and psychological symptoms in men and women with schizophrenia, including women with treatment refractory psychosis. These outcomes together with potent neurocognitive, neuroprotective, and cardiometabolic properties suggest that SERMs could be the potential targets for designing effective and safer therapies for psychiatric disorders.

Hearts and Minds: Real-Life Cardiotoxicity With Clozapine in Psychosis.

Schizophrenia has a 1% prevalence in the population; 30% of these patients are treatment refractory. Clozapine is the only drug licensed to treat treatment refractory psychosis, but concerns about potential adverse effects result in only a proportion of eligible patients being treated. Although a well-documented neutropenia risk is mitigated by routine blood testing, cardiac toxicity is a commonly cited reason to discontinue clozapine treatment. However, there is little data on the real-life cardiac outcomes in those receiving clozapine treatment. Retrospective review of electrocardiogram, echocardiogram, and clinical outcomes in 39 inpatients with treatment-refractory schizophrenia, treated with clozapine and other antipsychotic medication, referred for cardiology opinion. Commonest reasons for referral were development of left ventricular (LV) impairment or sinus tachycardia with normal LV function. Patients were reviewed by a range of cardiologists, receiving varied interventions.Median LV ejection fraction in the clozapine group was normal (52%). Serial echocardiograms demonstrated that clozapine-treated patients with LV impairment had no change in LV ejection fraction over a 4-month follow-up. Left ventricular ejection fraction did not differ between patients treated with clozapine and other antipsychotics. However, over an 11-year follow-up period, 48% of patients had discontinued clozapine treatment. This naturalistic study demonstrates that clozapine is not associated with significant cardiac mortality or morbidity. There is a real need for multidisciplinary working between specialist cardiologists and psychiatrists caring for these complex patients to facilitate optimal long-term physical and mental health outcomes.

Clinical response to electroconvulsive therapy among patients with treatment-refractory psychosis: the BC Psychosis Program experience

Clinical response to electroconvulsive therapy among patients with treatment-refractory psychosis: the BC Psychosis Program experience

Prevalence of serum N-methyl-D-aspartate receptor autoantibodies in refractory psychosis.

N-methyl-d-aspartate receptor (NMDA-R) autoantibodies have been reported in people with acute psychosis. We hypothesised that their presence may be implicated in the aetiology of treatment-refractory psychosis. We sought to ascertain the point prevalence of NMDA-R antibody positivity in patients referred to services for treatment-refractory psychosis. We found that 3 (7.0%) of 43 individuals had low positive NMDA-R antibody titres. This suggests that NMDA-R autoantibodies are unlikely to account for a large proportion of treatment-refractory psychosis.

Unheard voices: outcomes of tertiary care for treatment-refractory psychosis.

Aims and method In up to a quarter of patients, schizophrenia is resistant to standard treatments. We undertook a naturalistic study of 153 patients treated in the tertiary referral in-patient unit of the National Psychosis Service based at the Maudsley Hospital in London. A retrospective analysis of symptoms on admission and discharge was undertaken using the OPCRIT tool, along with preliminary economic modelling of potential costs related to changes in accommodation.Results In-patient treatment demonstrated statistically significant improvements in all symptom categories in patients already identified as having schizophrenia refractory to standard secondary care. The preliminary cost analysis showed net savings to referring authorities due to changes from pre- to post-discharge accommodation.Clinical implications Despite the enormous clinical, personal and societal burden of refractory psychotic illnesses, there is insufficient information on the outcomes of specialised tertiary-level care. Our pilot data support its utility in all domains measured.

Symptom changes in five dimensions of the Positive and Negative Syndrome Scale in refractory psychosis

Refractory psychosis units currently have little information regarding which symptoms profiles should be expected to respond to treatment. In the current study, we provide this information using structural equation modeling of Positive and Negative Syndrome Scale (PANSS) ratings at admission and discharge on a sample of 610 patients admitted to a treatment refractory psychosis program at a Canadian tertiary care unit between 1990 and 2011. The hypothesized five-dimensional structure of the PANSS fit the data well at both admission and discharge, and the latent variable scores are reported as a function of symptom dimension and diagnostic category. The results suggest that, overall, positive symptoms (POS) responded to treatment better than all other symptoms dimensions, but for the schizoaffective and bipolar groups, greater response on POS was observed relative to the schizophrenia and major depression groups. The major depression group showed the most improvement on negative symptoms and emotional distress, and the bipolar group showed the most improvement on disorganization. Schizophrenia was distinct from schizoaffective disorder in showing reduced treatment response on all symptom dimensions. These results can assist refractory psychosis units by providing information on how PANSS symptom dimensions respond to treatment and how this depends on diagnostic category.

W07-02 - Improving tolerability of clozapine

Clozapine is uniquely effective in the management of treatment-refractory psychosis. However, many patients who are eligible to receive clozapine do not receive it, either because they have previously experienced adverse effects, or because of a reluctance to undergoing mandatory blood monitoring. At the National Psychosis Unit, a service designed for patients with treatment refractory psychosis, we specialise in helping patients to start to re-start clozapine under these circumstances. This presentation will combine research evidence and our own experience on the National Psychosis Unit to offer advice on improving the acceptability and tolerability of clozapine. I will cover common but troublesome problems such as hypersalivation and sedation, as well as the approach to re-challenging patients who have previously experienced suspected blood dyscrasias or cardiovascular complications of clozapine.

Temporal lobe epilepsy masquerading as psychosis – a case report and literature review

The psychoses of epilepsy are well recognized complications of seizure disorders, diagnosed easily from the history. However, in the absence of recognized seizures, the diagnosis can be challenging. We present a 27-year-old female, who suffered a treatment refractory psychosis for 6 years. She did not report, or display, any seizure activity, and extensive investigation was unremarkable. The onset of new symptoms prompted a repeat work-up which clinched the diagnosis of psychosis of epilepsy. Treatment with Lamotrigine and Amisulpiride achieved an excellent response, and she has remained symptom free for 7 months. We conclude with a brief literature review.

Better pharmacotherapy for schizophrenia: What does the future hold?

Despite the expansion of available antipsychotic drugs over the past 50 years, functional outcomes for individuals with schizophrenia have not markedly improved. These agents are efficacious for psychosis but do not adequately address other core domains of schizophrenia psychopathology, namely negative symptoms and cognitive impairment, which have a greater impact on functional outcomes, including vocational or academic performance and interpersonal relationships. In addition, treatment-refractory psychosis still precludes functional improvement in many patients. Schizophrenia is a clinical syndrome consisting of these domains, which likely have some disparities in their respective pathophysiologies. This suggests that drug development should look to other molecular targets besides the D2 receptor, which characterizes the mechanism of available medications for schizophrenia. In this report, we review novel pharmacologic approaches that aim to specifically address each individual domain of schizophrenia. The goal of this future pharmacotherapy strategy is to advance outcomes beyond psychosis remission and toward functional recovery.

Clozapine-Resistant Psychosis, Smoking, and Caffeine: Managing the Neglected Effects of Substances That Our Patients Consume Every Day

More than 30% of patients with psychotic disorders who are refractory to antipsychotic treatment also fail to respond to clozapine. Despite the high prevalence of smoking and caffeine use in the psychiatric population, these habits are usually overlooked as factors contributing to antipsychotic treatment failure. We describe 2 male patients with severe treatment-resistant psychosis, one with schizophrenia and the other with bipolar affective disorder-both of whom smoked heavily, and the latter also consumed enormous amounts of caffeine-whose symptoms were refractory to clozapine. Both patients experienced a major, sustained amelioration of their psychotic symptoms when clozapine treatment was recommenced under supervision in the inpatient setting and the pharmacological interactions between clozapine, smoking, and caffeine were considered. Therapeutic strategies included gradual increases in daily doses of clozapine, monitoring clozapine plasma levels, using single daily doses of clozapine at night, and augmenting clozapine treatment with low doses of amisulpride, a selective antagonist at the dopamine D2 and D3 receptors. Smoking and excessive caffeine use are associated with poor therapeutic responses to clozapine and should be considered in the pharmacological management of treatment-refractory psychosis, regardless of the primary diagnosis.

Psychosis Due to Neurologic Conditions.

Psychosis arises with considerable frequency in a number of neurologic conditions. The treatment of such patients is often challenging, as many of the treatments for psychosis pose some risk of worsening the underlying neurologic condition. Although psychosis may emerge in the context of any neurologic condition that sufficiently disrupts the functioning of or connections between limbic, paralimbic, frontal, subcortical areas mediating complex sensory perception, interpretation, and thought or language organization, secondary psychoses are most often encountered in patients with Alzheimer's disease (Parkinson's disease receives dopaminomimetic therapies) and epilepsy. Psychosis, and particularly delusions and visual hallucinations, may arise in Alzheimer's disease. Based on the available literature, the first-line therapy for this problem is risperidone 0.5 to 3 mg per day. If this treatment proves unsuccessful, low-dose haloperidol or olanzapine should be considered next. If these treatments prove unsuccessful, quetiapine should then be considered. Finally, clozapine may be useful for treatment-refractory psychosis due to Alzheimer's disease, but due caution is warranted given its considerable anticholinergic properties and potential for worsening cognition in these patients. Although disease-emergent psychosis (paranoid delusions and visual hallucinations) may develop in patients with Parkinson's disease, psychosis due to dopaminomimetic therapy is much more common. When such symptoms develop, the accepted first step is to taper anti-parkinsonian medications were possible. Anticholinergic medications, amantadine, selegiline, and dopamine receptor agonists should be reduced or discontinued, provided that the patient can tolerate changes in motor symptoms attendant to such reductions. When these reductions are not feasible or fail to improve treatment-emergent psychosis, low-dose quetiapine or clozapine may be useful. The greatest body of evidence supports the effectiveness of these treatments and their relative lack of adverse effects on motor function. When psychosis develops in the context of epilepsy, the generally accepted first step is to maximize anticonvulsant therapy in an effort to reduce the possible contribution of electrophysiologic disturbances in the described areas to psychotic symptoms. When interictal psychosis persists despite such adjustments, initiation with low-dose atypical antipsychotics carries the least risk of lowering seizure threshold and should be considered.