| 1 | Psychopharmacology (Berl.) 2000 Oct 152: 312-20 |
|---|---|
| PMID | 11105942 |
| Title | Effects of noradrenaline depletion in the brain on response on novelty in isolation-reared rats. |
| Abstract | Social isolation from weaning in the rat produces a variety of neurochemical and behavioural effects in the adult that in part parallel changes seen in human schizophrenia. The study investigated the effects of central noradrenaline (NA) depletion by the selective neurotoxin, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4), on the behaviour of isolation-reared rats. Male Lister hooded rats were reared singly or in groups after weaning. During week 2, the rats were tested in photocell activity cages and were then injected with DSP-4 (25 mg/kg, IP). During week 4, rats were tested in the open field under the following conditions: open field alone, with two novel stimuli (T1), and with a familiar and a novel object (T2), and in the activity cages. DSP-4 significantly reduced cortical and hippocampal NA levels with no effect on the hypothalamus. Isolation-reared rats exhibited locomotor hyperactivity and reduced habituation to the testing arena, although their exploration of the novel objects in T1 was not significantly different from group-reared rats. DSP-4 treatment in group-reared rats increased inner zone activity in the open field but did not significantly affect the exploration of novel objects. DSP-4 treatment in isolates reduced exploration of objects at T2 while increasing exploration of the general environment. Isolation rearing influences the behavioural effects of central NA depletion. The results suggest isolation-induced changes in the central noradrenergic system in the isolated rat, supporting the view that early environmental factors can have long-term effects on central noradrenergic function as well as other neurotransmitter systems. |
| SCZ Keywords | schizophrenia, schizophrenias |
| 2 | Nord J Psychiatry 2002 -1 56: 319-27 |
| PMID | 12470304 |
| Title | Symptom dimensions and their association with outcome and treatment setting in long-term schizophrenia. Results of the DSP project. |
| Abstract | National representative samples of 1571 schizophrenia patients discharged from mental hospitals in Finland in 1990 and 1994 were interviewed 3 years after discharge. The symptom items assessed by the PANSS were factorized and orthogonal rotations were performed. Five factor dimensions, negative, positive, depressive, hostile and disorganization dimension, were obtained and correlated with data of patients' socio-demographic background, clinical history, condition and outcome. The negative dimension was more prominent in male and single patients, the depressive dimension in female and divorced patients. Patients with early onset and long duration of illness had high disorganization scores. Patients with disorganized subtype of schizophrenia had high scores in positive and disorganization dimensions. High scores in all, especially in negative and positive dimensions, were associated with poor psychosocial situation. Symptom dimensions varied also according to treatment setting at follow-up. Symptom dimensions of long-term schizophrenia patients in the community are closely associated with patients' socio-demographic background, clinical history and conditions, as well as with outcome and the treatment patients receive. A dimensional approach, instead of a categorical one, seems to be important in assessing symptomatology and its relation to outcome and interventions in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenias |
| 3 | Eur. Psychiatry 2003 Oct 18: 274-81 |
| PMID | 14611921 |
| Title | Women have later onset than men in schizophrenia--but only in its paranoid form. Results of the DSP project. |
| Abstract | According to the literature, schizophrenia begins in men earlier than in women. It has been argued that the gender-bound age difference is due to the protective antidopaminergic effect of estrogens in women. However, the effect of gender on the age of onset may vary between different types of schizophrenias, and can also be modulated by marital status and by age at onset of illness. Comprehensive data were collected on 3306 DSM IIR schizophrenia patients, aged 15-64 years, who had been discharged from psychiatric hospitals in Finland in 1982, 1986 and 1990. The age of onset of illness (AOI) was defined by the age at the first admission (AFA). Male patients were admitted earlier than female patients, and a small second peak in women appeared at the age of 40-44. However, there were no gender differences in AFA within diagnostic subgroups, except in paranoid schizophrenia in which AFA was lower in men than in women even when marital status was taken into account. Within paranoid schizophrenia, this effect of gender was significant only in those of the patients whose AFA was higher than 30 years. It is suggested that there is no gender difference in AOI in early onset schizophrenia. In later onset, paranoid schizophrenia, the illness seems to manifest in women later than in men. |
| SCZ Keywords | schizophrenia, schizophrenias |
| 4 | Eur. Psychiatry 2003 Oct 18: 274-81 |
| PMID | 14611921 |
| Title | Women have later onset than men in schizophrenia--but only in its paranoid form. Results of the DSP project. |
| Abstract | According to the literature, schizophrenia begins in men earlier than in women. It has been argued that the gender-bound age difference is due to the protective antidopaminergic effect of estrogens in women. However, the effect of gender on the age of onset may vary between different types of schizophrenias, and can also be modulated by marital status and by age at onset of illness. Comprehensive data were collected on 3306 DSM IIR schizophrenia patients, aged 15-64 years, who had been discharged from psychiatric hospitals in Finland in 1982, 1986 and 1990. The age of onset of illness (AOI) was defined by the age at the first admission (AFA). Male patients were admitted earlier than female patients, and a small second peak in women appeared at the age of 40-44. However, there were no gender differences in AFA within diagnostic subgroups, except in paranoid schizophrenia in which AFA was lower in men than in women even when marital status was taken into account. Within paranoid schizophrenia, this effect of gender was significant only in those of the patients whose AFA was higher than 30 years. It is suggested that there is no gender difference in AOI in early onset schizophrenia. In later onset, paranoid schizophrenia, the illness seems to manifest in women later than in men. |
| SCZ Keywords | schizophrenia, schizophrenias |
| 5 | Eur. Psychiatry 2007 Jul 22: 313-8 |
| PMID | 17188843 |
| Title | Body mass index and functioning in long-term schizophrenia. Results of the DSP project. |
| Abstract | The study evaluates the association of body mass index (BMI) with functioning in male and female patients with long-term schizophrenia. 722 long-term schizophrenia patients were interviewed three years after discharge from hospital. Their weight and height were recorded and data on their background, illness history, psychosocial functioning (Global Assessment Scale; GAS), health behaviour, daily doses of neuroleptics, and psychiatric symptoms were collected. BMI correlated significantly with GAS scores in male (r=0.202, p=0.000) but not in female patients. In male patients, BMI associated significantly (p=0.005) with GAS scores even when the effects of psychiatric symptoms and other confounding variables were taken into account. In male but not in female long-term patients with schizophrenia, low BMI associates with poor functioning. It is suggested that among male schizophrenia patients, low BMI may be an indicator of poor functioning. |
| SCZ Keywords | schizophrenia, schizophrenias |
| 6 | Psychiatry Res 2008 Jul 160: 38-46 |
| PMID | 18514323 |
| Title | Patterns of stress in schizophrenia. |
| Abstract | Although it is widely recognized that stress plays a key role in the pathophysiology of schizophrenia, little is known regarding the particular types of stress patients experience. Less is known about the interplay among stressful events, personality mediators, and emotional responses. In this study, we investigated 10 stress dimensions in 29 patients with schizophrenia and 36 healthy volunteers using the Derogatis Stress Profile (DSP), and the relationship between these dimensions and symptoms in patients. Overall, patients had an approximate 0.75 standard deviation increase in stress compared with healthy volunteers. Significant increases in stress among patients compared with healthy volunteers were observed specifically in areas related to domestic environment, driven behavior, and depression, but not in health, attitude posture, time pressure, relaxation potential, role definition, hostility, or anxiety. More DSP-rated depression among patients correlated significantly with greater negative symptom severity. Patients with a shorter duration of antipsychotic drug exposure had significantly greater hostility than did patients with a longer duration of exposure, but did not differ in any other dimension. Continued investigation of domestic environmental stressors, driven behavior, and depression may be useful in identifying high-risk groups, and understanding symptom exacerbation and precipitants of relapse in patients already diagnosed with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenias |
| 7 | Int. J. Neuropsychopharmacol. 2011 Feb 14: 53-68 |
| PMID | 20701825 |
| Title | Selective enhancement of mesocortical dopaminergic transmission by noradrenergic drugs: therapeutic opportunities in schizophrenia. |
| Abstract | The superior efficacy of atypical vs. classical antipsychotic drugs to treat negative symptoms and cognitive deficits in schizophrenia appears related to their ability to enhance mesocortical dopamine (DA) function. Given that noradrenergic (NE) transmission contributes to cortical DA output, we assessed the ability of NE-targeting drugs to modulate DA release in medial prefrontal cortex (mPFC) and nucleus accumbens (NAc), with the aim of selectively increasing mesocortical DA. Extracellular DA was measured using brain microdialysis in rat mPFC and NAc after local/systemic drug administration, electrical stimulation and selective brain lesions. Local GBR12909 [a selective DA transporter (DAT) inhibitor] administration increased DA output more in NAc than in mPFC whereas reboxetine [a selective NE transporter (NET) inhibitor] had an opposite regional profile. DA levels increased comparably in both regions of control rats after local nomifensine (DAT+NET inhibitor) infusion, but this effect was much lower in PFC of NE-lesioned rats (DSP-4) and in NAc of 6-OHDA-lesioned rats. Electrical stimulation of the locus coeruleus preferentially enhanced DA output in mPFC. Consistently, the administration of reboxetine+RX821002 (an ?2-adrenoceptor antagonist) dramatically enhanced DA output in mPFC (but not NAc). This effect also occurred when reboxetine+RX821002 were co-administered with haloperidol or clozapine. The preferential contribution of the NE system to PFC DA allows selective enhancement of DA transmission by simultaneously blocking NET and ?2-adrenoceptors, thus preventing the autoreceptor-mediated negative feedback on NE activity. Our results highlight the importance of NET and ?2-adrenoceptors as targets for treating negative/cognitive symptoms in schizophrenia and related psychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenias |
| 8 | Psychopharmacology (Berl.) 2013 Oct 229: 665-71 |
| PMID | 23657424 |
| Title | Benzodiazepine therapy in psychiatric outpatients is associated with deliberate self-poisoning events at emergency departments-a population-based nested case-control study. |
| Abstract | Deliberate self-poisoning (DSP), the most common form of deliberate self-harm, is closely associated with suicide. Identifying risk factors of DSP is necessary for implementing prevention strategies. This study aimed to evaluate the relationship between benzodiazepine (BZD) treatment in psychiatric outpatients and DSP cases at emergency departments (EDs). We performed a retrospective nested case-control study of psychiatric patients receiving BZD therapy to evaluate the relationship between BZD use and the diagnosis of DSP at EDs using data from the nationwide Taiwan National Health Insurance Research Database. Regression analysis yielded an odds ratio (OR) and 95 % confidence interval (95 % CI) indicating that the use of BZDs in psychiatric outpatients was significantly associated with DSP cases at EDs (OR?=?4.46, 95 % CI?=?3.59-5.53). Having a history of DSP, sleep disorders, anxiety disorders, schizophrenia, depression, or bipolar disorder was associated with a DSP diagnosis at EDs (OR?=?13.27, 95 % CI?=?8.28-21.29; OR?=?5.04, 95 % CI?=?4.25-5.98; OR?=?3.95, 95 % CI?=?3.32-4.70; OR?=?7.80, 95 % CI?=?5.28-11.52; OR?=?15.20, 95 % CI?=?12.22-18.91; and OR?=?18.48, 95 % CI?=?10.13-33.7, respectively). After adjusting for potential confounders, BZD use remained significantly associated with a subsequent DSP diagnosis (adjusted OR?=?2.47, 95 % CI?=?1.93-3.17). Patients taking higher average cumulative BZD doses were at greater risk of DSP. Vigilant evaluation of the psychiatric status of patients prescribed with BZD therapy is critical for the prevention of DSP events at EDs. |
| SCZ Keywords | schizophrenia, schizophrenias |
| 9 | J Clin Psychopharmacol 2013 Jun 33: 398-404 |
| PMID | 23609386 |
| Title | Optimal extent of dopamine D2 receptor occupancy by antipsychotics for treatment of dopamine supersensitivity psychosis and late-onset psychosis. |
| Abstract | Several studies have proposed an optimal dopamine D2 receptor occupancy by antipsychotics (OOc) to establish optimal pharmacological treatment of schizophrenia. However, there are limitations to the use of the OOc, especially in application to patients with treatment-resistant schizophrenia, including dopamine supersensitivity psychosis (DSP) or late-onset psychosis (LOP). It has been suggested that D2 receptor density is up-regulated by chronic treatment of antipsychotics in DSP, whereas it may be low in LOP owing to age-related reduction. In estimation of the proposed OOc, these alterations have not been taken into account, which may be one of the factors contributing to the limited application of this index. We here hypothesize that there is an optimal range in the number of D2 receptors available for dopamine binding to elicit adequate neurotransmission in the treatment of patients with schizophrenia. We then estimated the OOc under the assumption that the range is constant while D2 density is variable. The results showed that the OOc and plasma level of antipsychotics increase with an increase in the D2 density but decrease with a decrease in the D2 density. That is, if the range of OOc is 65% to 78% in a standard D2 density, it becomes 82% to 89% under 2-fold up-regulated density and 42% to 63% under a 40% reduced density. The results also indicated that the reduction of the plasma antipsychotic level is greater during a given time period in patients with higher D2 density, as they need a higher antipsychotic dose to achieve the raised OOc, which would account for the clinical features of DSP, for example, acute exacerbation after a discontinuation of antipsychotics. On the other hand, in patients with lower D2 density, only a lower antipsychotic dose will achieve the OOc, and a small increase in the dose will result in a greater increase in occupancy and induce extrapyramidal adverse effects more easily. Furthermore, the reduction of the plasma antipsychotic level during the time period is smaller, which prolongs extrapyramidal adverse effects after discontinuation of antipsychotics in LOP. We also attempted to develop a strategy for the prevention and treatment of patients with DSP or LOP by focusing on D2 density. |
| SCZ Keywords | schizophrenia, schizophrenias |
| 10 | Schizophr. Res. 2014 May 155: 52-8 |
| PMID | 24667073 |
| Title | A prospective comparative study of risperidone long-acting injectable for treatment-resistant schizophrenia with dopamine supersensitivity psychosis. |
| Abstract | Dopamine supersensitivity psychosis (DSP) is considered to be one cause of treatment-resistant schizophrenia (TRS). The authors investigated the efficacy of risperidone long-acting injections (RLAI) in patients with TRS and DSP. This is a multicenter, prospective, 12-month follow-up, observational study that included unstable and severe TRS patients with and without DSP. 115 patients with TRS were recruited and divided into two groups according to the presence or absence of DSP which was judged on the basis of the clinical courses and neurological examinations. RLAI was administered adjunctively once every 2weeks along with oral antipsychotics. We observed changes in scores for the Brief Psychiatric Rating Scales (BPRS), Clinical Global Impression-Severity of Illness (CGI-S), Global Assessment of Functioning Scale (GAF), and Extrapyramidal Symptom Rating Scale (ESRS) during the study. Of the assessed 94 patients, 61 and 33 were categorized into the DSP and NonDSP groups, respectively. While baseline BPRS total scores, CGI-S scores and GAF scores did not differ, the ESRS score was significantly higher in the DSP group compared with the NonDSP group. Treatment significantly reduced BPRS total scores and CGI-S scores, and increased GAF scores in both groups, but the magnitudes of change were significantly greater in the DSP group relative to the NonDSP group. ESRS scores were also reduced in the DSP group. Responder rates (?20% reduction in BPRS total score) were 62.3% in the DSP group and 21.2% in the NonDSP group. It is suggested that DSP contributes to the etiology of TRS. Atypical antipsychotic drugs in long-acting forms, such as RLAI, can provide beneficial effects for patients with DSP. UMIN (UMIN000008487). |
| SCZ Keywords | schizophrenia, schizophrenias |
| 11 | Neuropsychiatr Dis Treat 2015 -1 11: 1845-51 |
| PMID | 26251601 |
| Title | Genetic association between G protein-coupled receptor kinase 6/?-arrestin 2 and dopamine supersensitivity psychosis in schizophrenia. |
| Abstract | Dopamine supersensitivity psychosis (DSP), clinically characterized by unstable and severe psychosis or tardive dyskinesia and often categorized as treatment-resistant schizophrenia, is promoted by long-term antipsychotic treatment. An upregulation of the dopamine D2 receptor caused by antipsychotic(s) is involved in the development of DSP. The present study explored the potential roles of G protein-coupled receptor kinase 6 (GRK6) and ?-arrestin 2 (ARRB2) that are involved in the trafficking of DRD2 in patients with DSP. We conducted a genetic association study of GRK6/ARRB2 between the patients with DSP episodes [DSP(+) group: N=108] and the patients without DSP(-) episodes [DSP(-) group: N=169] from the total group of patients (N=333). Based on the patients' treatment history, a DSP episode was defined as withdrawal psychosis, developed tolerance to antipsychotic effect, and tardive dyskinesia (the remaining 56 patients were excluded due to insufficient information). The results revealed that none of the allelic or genotyping distributions of five single nucleotide polymorphisms (SNPs) of GRK6 and three SNPs of ARRB2 showed any significant difference between the DSP(+) and DSP(-) groups. The results suggest that the SNP analyses of these two molecules fail to classify patients into the potential clinical subtype of DSP(+) or DSP(-) group. However, since GRK6 and ARRB2 are surely involved in dopamine D2 receptor metabolism, further studies based on prospective observations of the onset of DSP under specific antipsychotic treatments are needed. |
| SCZ Keywords | schizophrenia, schizophrenias |
| 12 | Int J Mol Sci 2015 -1 16: 30144-63 |
| PMID | 26694375 |
| Title | Alterations of Dopamine D2 Receptors and Related Receptor-Interacting Proteins in Schizophrenia: The Pivotal Position of Dopamine Supersensitivity Psychosis in Treatment-Resistant Schizophrenia. |
| Abstract | Although the dopamine D2 receptor (DRD2) has been a main target of antipsychotic pharmacotherapy for the treatment of schizophrenia, the standard treatment does not offer sufficient relief of symptoms to 20%-30% of patients suffering from this disorder. Moreover, over 80% of patients experience relapsed psychotic episodes within five years following treatment initiation. These data strongly suggest that the continuous blockade of DRD2 by antipsychotic(s) could eventually fail to control the psychosis in some point during long-term treatment, even if such treatment has successfully provided symptomatic improvement for the first-episode psychosis, or stability for the subsequent chronic stage. Dopamine supersensitivity psychosis (DSP) is historically known as a by-product of antipsychotic treatment in the manner of tardive dyskinesia or transient rebound psychosis. Numerous data in psychopharmacological studies suggest that the up-regulation of DRD2, caused by antipsychotic(s), is likely the mechanism underlying the development of the dopamine supersensitivity state. However, regardless of evolving notions of dopamine signaling, particularly dopamine release, signal transduction, and receptor recycling, most of this research has been conducted and discussed from the standpoint of disease etiology or action mechanism of the antipsychotic, not of DSP. Hence, the mechanism of the DRD2 up-regulation or mechanism evoking clinical DSP, both of which are caused by pharmacotherapy, remains unknown. Once patients experience a DSP episode, they become increasingly difficult to treat. Light was recently shed on a new aspect of DSP as a treatment-resistant factor. Clarification of the detailed mechanism of DSP is therefore crucial, and a preventive treatment strategy for DSP or treatment-resistant schizophrenia is urgently needed. |
| SCZ Keywords | schizophrenia, schizophrenias |
| 13 | Psychiatry Res 2015 Jun 227: 278-82 |
| PMID | 25863824 |
| Title | Dopamine supersensitivity psychosis as a pivotal factor in treatment-resistant schizophrenia. |
| Abstract | There may be subtypes in treatment-resistant schizophrenia (TRS), and one of the subtypes may be related to dopamine supersensitivity psychosis (DSP). In developing strategies for prevention and treatment TRS, it is important to clarify the role of DSP in TRS. TRS patients were recruited from 3 hospitals for the present study. Through chart reviews, all patients were judged as either TRS or not, and then possible TRS patients were investigated about their past/present histories of DSP episode(s) by direct interviews. We then compared each factor between the groups with and without DSP episode(s). Out of 611 patients screened, 147 patients met the criteria for TRS and were included in the present analysis. These were divided into groups with and without DSP, comprising 106 (72.1%) and 41 patients (27.9%), respectively. Clinical characteristics in the two groups were similar, except for drug-induced movement disorders (DIMDs), which were significantly more important in DSP patients. Of the DSP patients, 42% and 56% experienced rebound psychosis and tolerance to antipsychotic effects, respectively. The present study revealed that approximately 70% of TRS patients experienced one or more DSP episodes, which may have a strong impact on the long-term prognosis of patients with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenias |
| 14 | J. Psychopharmacol. (Oxford) 2015 Apr 29: 383-9 |
| PMID | 25735995 |
| Title | Dopamine supersensitivity psychosis and dopamine partial agonist: a retrospective survey of failure of switching to aripiprazole in schizophrenia. |
| Abstract | The administration of aripiprazole (ARI), a dopamine partial agonist, could provoke abrupt psychotic worsening in patients with schizophrenia. We explored the relationship between this psychotic worsening and dopamine supersensitivity psychosis (DSP), which is a clinically vulnerable state. We conducted a retrospective investigation for 264 patients whose treatment medication was switched to ARI from other antipsychotics. We divided the patients into the DSP(+) group with a history of DSP episode(s) (N = 70) and the DSP(-) group without such a history (N = 194), and then compared the clinical factors relevant to the success or failure of the switch to ARI between them. The results revealed that patients in the DSP(+) group experienced psychotic worsening following the switch to ARI with a significant higher rate compared to the DSP(-) group (23% vs. 8%, P < 0.01). Moreover, the dosages of the drugs before the ARI introduction in the patients experiencing the psychotic worsening in the DSP (-) group were higher than those in other patients of the group. Our findings suggest that patients who receive high dosages of antipsychotic drugs form overt or covert DSP and such state is highly associated with psychotic worsening following ARI treatment. |
| SCZ Keywords | schizophrenia, schizophrenias |
| 15 | Curr Top Behav Neurosci 2016 Feb -1: -1 |
| PMID | 26857462 |
| Title | Neuroteratology and Animal Modeling of Brain Disorders. |
| Abstract | Over the past 60 years, a large number of selective neurotoxins were discovered and developed, making it possible to animal-model a broad range of human neuropsychiatric and neurodevelopmental disorders. In this paper, we highlight those neurotoxins that are most commonly used as neuroteratologic agents, to either produce lifelong destruction of neurons of a particular phenotype, or a group of neurons linked by a specific class of transporter proteins (i.e., dopamine transporter) or body of receptors for a specific neurotransmitter (i.e., NMDA class of glutamate receptors). Actions of a range of neurotoxins are described: 6-hydroxydopamine (6-OHDA), 6-hydroxydopa, DSP-4, MPTP, methamphetamine, IgG-saporin, domoate, NMDA receptor antagonists, and valproate. Their neuroteratologic features are outlined, as well as those of nerve growth factor, epidermal growth factor, and that of stress. The value of each of these neurotoxins in animal modeling of human neurologic, neurodegenerative, and neuropsychiatric disorders is discussed in terms of the respective value as well as limitations of the derived animal model. Neuroteratologic agents have proven to be of immense importance for understanding how associated neural systems in human neural disorders may be better targeted by new therapeutic agents. |
| SCZ Keywords | schizophrenia, schizophrenias |
| 16 | Schizophr. Res. 2016 Feb 170: 252-8 |
| PMID | 26775264 |
| Title | Impact of dopamine supersensitivity psychosis in treatment-resistant schizophrenia: An analysis of multi-factors predicting long-term prognosis. |
| Abstract | Although a variety of factors are known to be significantly related to poor prognosis in schizophrenia, their interactions remain unclear. Dopamine supersensitivity psychosis (DSP) is a clinical concept related to long-term pharmacotherapy and could be one of the key factors contributing to the development of treatment-resistant schizophrenia (TRS). The present study aims to explore the effect of DSP on progression to TRS. Two-hundreds and sixty-five patients were classified into either a TRS or Non-TRS group based on retrospective survey and direct interview. The key factors related to prognosis, including the presence or absence of DSP episodes, were extracted, and each factor was compared between the two groups. All parameters except for the duration of untreated psychosis (DUP) were significantly worse in the TRS group compared to the Non-TRS group. In particular, the TRS group presented with a significantly higher rate of DSP episodes than the Non-TRS group. Regression analysis supported the notion that DSP plays a pivotal role in the development of TRS. In addition, deficit syndrome was suggested to be a diagnostic subcategory of TRS. Our data confirmed that the key predicting factors of poor prognosis which have been established would actually affect somehow the development of TRS. In addition, the occurrence of a DSP episode during pharmacotherapy was shown to promote treatment refractoriness. |
| SCZ Keywords | schizophrenia, schizophrenias |