Neurobiochemical Disturbances in Psychosis and their Implications for Therapeutic Intervention.

Psychosis, marked by the emergence of psychotic symptoms, delves into the intricate dance of neurotransmitter dynamics, prominently featuring dopamine as a key orchestrator. In individuals living with psychotic conditions, the finely tuned balance of dopamine becomes disrupted, setting off a cascade of perceptual distortions and the manifestation of psychotic symptoms. A lot of factors can impact dopamine metabolism, further complicating its effects. From genetic predispositions to environmental stressors and inflammation, the delicate equilibrium is susceptible to various influences. The sensorium, the origin of incoming information, loses its intrinsic valence in this complex interplay. The concept of the "signal-to-noise ratio" encapsulates dopamine's role as a molecular switch in neural networks, influencing the flow of information serving the basic biological functions. This nuanced modulation acts as a cognitive prism, shaping how the world is perceived. However, in psychosis, this balance is disrupted, steering individuals away from a shared reality. Understanding dopamine's centrality requires acknowledging its unique status among neurotransmitters. Unlike strictly excitatory or inhibitory counterparts, dopamine's versatility allows it to toggle between roles and act as a cognitive director in the neural orchestra. Disruptions in dopamine synthesis, exchange, and receptor representation set off a chain reaction, impacting the delivery of biologically crucial information. The essence of psychosis is intricately woven into the delicate biochemical ballet choreographed by dopamine. The disruption of this neurotransmitter not only distorts reality but fundamentally reshapes the cognitive and behavioral field of our experience. Recognizing dopamine's role as a cognitive prism provides vital insights into the multifaceted nature of psychotic conditions, offering avenues for targeted therapeutic interventions aimed at restoring this delicate neurotransmitter balance.

Cognition in Patients with Schizophrenia: Interplay between Working Memory, Disorganized Symptoms, Dissociation, and the Onset and Duration of Psychosis, as Well as Resistance to Treatment.

Schizophrenia is traditionally associated with the presence of psychotic symptoms. In addition to these, cognitive symptoms precede them and are present during the entire course of the schizophrenia process. The present study aims to establish the relationship between working memory (short-term memory and attention), the features of the clinical picture, and the course of the schizophrenic process, gender distribution and resistance to treatment. METHODS: In total, 105 patients with schizophrenia were observed. Of these, 66 were women and 39 men. Clinical status was assessed using the Positive and Negative Syndrome Scale (PANSS), Brief Psychiatric Rating Scale (BPRS), Dimensional Obsessive-Compulsive Symptom Scale (DOCS), scale for dissociative experiences (DES) and Hamilton Depression Rating Scale (HAM-D)-cognitive functions using the Luria 10-word test with fixation assessment, reproduction and attention analysis. The clinical evaluation of resistance to the treatment showed that 45 patients were resistant to the ongoing medical treatment and the remaining 60 had an effect from the therapy. RESULTS: Our study showed that, in most patients, we found disorders of working memory and attention. In 69.82% of the patients, we found problems with fixation; in 38.1%, problems with reproduction; and in 62.86%, attention disorders. Conducting a regression analysis showed that memory and attention disorders were mainly related to the highly disorganized symptoms scale, the duration of the schizophrenic process and the dissociation scale. It was found that there was a weaker but significant association between the age of onset of schizophrenia and negative symptoms. In the patients with resistant schizophrenia, much greater violations of the studied parameters working memory and attention were found compared to the patients with an effect from the treatment. CONCLUSION: Impairments in working memory and attention are severely affected in the majority of patients with schizophrenia. Their involvement is most significant in patients with resistance to therapy. Factors associated with the highest degree of memory and attention impairment were disorganized symptoms, duration of schizophrenia, dissociative symptoms and, to a lesser extent, onset of illness. This analysis gives us the right to consider that the early and systematic analysis of cognition is a reliable marker for tracking both clinical dynamics and the effect of treatment.

An expert review of clozapine in Eastern European countries: Use, regulations and pharmacovigilance.

OBJECTIVES: To compare the prevalence, regulations, and pharmacovigilance practices of clozapine use in Eastern European countries (except Russia). METHODS: Questionnaires and data from administrative databases (2016 and 2021), package inserts and national guidelines were collected from 21 co-authors from 21 countries. Reports of clozapine adverse drug reactions (ADRs) sent to the global pharmacovigilance database (VigiBase™) were analyzed from introduction to December 31, 2022. RESULTS: Clozapine prescription among antipsychotics in 2021 varied six-fold across countries, from 2.8 % in the Czech Republic to 15.8 % in Montenegro. The utilization of antipsychotics in both 2016 and 2021 was highest in Croatia, and lowest in Serbia in 2016, and Montenegro in 2021, which had half the defined daily dose (DDD)/1000/day compared to the Croatian data. From 2016 to 2021, the prevalence of antipsychotic use increased in almost all countries; the proportion of clozapine use mainly remained unchanged. Differences were detected in hematological monitoring requirements and clozapine approved indications. Only a few national schizophrenia guidelines mention clozapine-induced myocarditis or individual titration schemes. The VigiBase search indicated major underreporting regarding clozapine and its fatal outcomes. By comparison, the United Kingdom had less than half the population of these Eastern European countries but reported to VigiBase more clozapine ADRs by 89-fold and clozapine fatal outcomes by almost 300-fold. CONCLUSION: Clozapine is under-utilized in Eastern European countries. Introducing individualized clozapine treatment schedules may help to maximize clozapine benefits and safety. Major improvement is needed in reporting clozapine ADRs and fatal outcomes in Eastern European countries.

Obsessive-compulsive symptoms in patient with schizophrenia: The influence of disorganized symptoms, duration of schizophrenia, and drug resistance.

Background: Schizophrenia is a chronic mental disorder with a many-faced clinical presentation. Obsessive-compulsive symptoms are often part of it. The characteristics of the clinical picture and the course of schizophrenia are factors related to both the resistance and the manifestation of obsessive-compulsive symptoms. Our study aims to establish the relationship between the peculiarities of the schizophrenia process and the influence of resistance on the expression of obsessive-compulsive symptoms. Methods: A study was conducted on 105 patients with schizophrenia. Of them, 39 are men and 66 are women. The evaluation of the effectiveness of the treatment showed that 45 were resistant to the applied therapy, while the remaining 60 responded. Clinical assessment of patients was performed using the Positive and Negative Syndrome Scale (PANSS) and Brief Psychiatric Rating Scale (BPRS). Assessment of obsessive-compulsive symptoms (OCS) was conducted with the Dimensional obsessive-compulsive symptoms scale (DOCS). Results: In 34% of all patients, we found clinically expressed obsessive-compulsive symptoms. In 40% of the patients with resistance, we found clinically expressed obsessive-compulsive symptoms, which are within the range of moderately expressed. In 30% of the patients in clinical remission, we found obsessive-compulsive symptoms, but mildly expressed. We found a statistically significant relationship between the severity of OCS and the disorganized symptoms and the duration of the schizophrenia process. No differences were found in the expression of OCS in patients of both sexes. Conclusion: We registered both an increased frequency and an increased expression of obsessive-compulsive symptoms in patients with resistant schizophrenia. These symptoms were positively associated with disorganized symptoms and duration of schizophrenia. No relationship was established with the positive, negative symptoms, as well as with the gender distribution.

Higher Depression Scores in Patients with Drug-Resistant Schizophrenia.

BACKGROUND: Schizophrenia is a mental illness with diverse clinical presentation, in which a significant proportion of patients show resistance to treatment. In patients with schizophrenia, symptoms from all psychotic and affective spectra are observed. On the one hand, affective symptoms determine the clinical course of schizophrenia and on the other hand, depressive symptoms are some of the most common ones in psychiatry in general. These data give us reason to explore the impact of depressive symptoms on the course of schizophrenia and its relationship with resistance to treatment. METHOD: A study of 105 patients with schizophrenia was performed. Of these, 39 were male and 66 were female. The evaluation of the effectiveness of the treatment carried out at 12 weeks of therapy showed that 45 were resistant to schizophrenia and the remaining 60 were in clinical remission. The clinical evaluation of the patients was performed with the PANSS (Positive and Negative Syndrome Scale) and BPRS (Brief Psychiatric Rating Scale) scales. The assessment of depressive complaints was conducted with the Hamilton Depression Scale. RESULTS: Our study showed that in the analysis of depressive complaints with the Hamilton scale females got 12.55 points, and males got 11.44 points. We found a correlation of depressive complaints with the evaluation on the PANSS and BPRS scales, and in the analysis on the individual subscales we found a correlation on the subscale for positive and disorganized symptoms and no correlation on the scale for negative symptoms. We established a difference in the level of depression in patients with resistance in whom the level of depressive complaints was 13.82, while in those in clinical remission it was 10.87 points. CONCLUSIONS: The level of depressive symptoms in patients with resistant schizophrenia is higher than in clinical remission. Depressive symptoms correlate with positive and disorganized symptoms on the PANSS scale, but not with negative symptoms. Gender is not a determining factor in depressive complaints.

Gender-associated role in patients with schizophrenia. Is there a connection with the resistance?

Schizophrenia is a chronic mental illness observed with equal prevalence in different cultures and ethnic groups. The clinical picture relates to behavior and social adaptation. A significant percentage of patients, despite the implementation of various therapeutic interventions, remain resistant to the ongoing treatment. Occupying a certain gender role depends both on biological belonging and on the way of self-perception characteristic of the given person. Self-perception reflects gender identification, which in social aspect is determined by the choice of social activities performed. Changes in behavior and social adaptation in patients with schizophrenia led us to conduct a study to analyze the perceived gender role in patients with schizophrenia, looking for differences between patients with treatment resistance and those in clinical remission. Materials and methods: A total of 105 patients with schizophrenia were analyzed. Of them, 45 were with resistant symptoms and 60 in clinical remission. The clinical analysis of the patients was carried out using the PANSS and BPRS scales. The evaluation of the choice of social activity related to a particular gender was done with the Bem Sex-Role Inventory (BSRI). Results: Out of all 105 patients with schizophrenia, in 80/76.19%/we found a higher identification with the female role, 17/16.19%/made an association with the male role and in 8/7.61%/patients we found the same results, i.e., with both the male and female roles. Among the patients with treatment resistant schizophrenia (TRS)-45, 34/75.56%/identified more with the female gender role, 6/13.33/perceived the male gender role as active, and in 5/11.11%/the identification was equal both with the male and with the female roles. Among the patients in clinical remission (CR)-60, 46/76.67%/accepted the female role as active, 11/18.33/identified with the male one, and three/5%/accepted both roles equally. When assessing the relationship between biological sex and perceived gender role, it was found that among men/a total of 39/half identified with the female gender role and half with the male gender role. Among women/a total of 66/, 90% perceived the female gender role, 7%-the male and 3% equally the male and the female gender role. No relationship was found between the choice of a certain gender role and the onset of psychosis and its duration in the observed patients. Conclusion: We found a higher percentage of schizophrenic patients who showed higher identification with the female gender role. Approximately half of the males identified with the female gender role. Resistance had no influence on the choice of sex-associated social activity. Factors related to the course of the schizophrenia process such as age of onset of psychosis and duration of psychosis was not associated with an influence on identification with sex-associated social activity. Our research suggests that identification with a particular sex associative social activity is most likely established earlier in the prodromal period.

Comparative Analysis of Lateral Preferences in Patients With Resistant Schizophrenia.

Background: Schizophrenia is a chronic brain disorder of diverse etiology and clinical presentation. Despite the expansion of treatment methods, between 30 and 50% of cases remain resistant to treatment. In patients with schizophrenia, specifics in the dominant lateralization in the brain function have been discovered. This gave a reason to seek the relation between functional lateralization and the effect of treatment. Methods: Of the 105 people observed with schizophrenia, 45 (42.9%) were treatment resistant, and 60 (57.1%) were considered responders. We compared functional lateralization (hand, foot, and eye) between the two groups. Handedness was ascertained by using the Edinburgh Handedness Inventory. The assessment was made at 12 weeks of treatment. Results: Of all patients with schizophrenia, 41.89% have mixed lateralization, 53.34% are right winged, and 4.76% of the patients are left winged. Resistance of the symptoms shows that 26 (57.78%) are cross-dominated, 18 (40%) are right winged, and 1 (2.22%) is left winged. In patients with clinical remission, 18 (30%) are of mixed dominance, 38 (63.33%) are right winged, and 4 (6.66%) are left winged. From the results for the separate lateralization of the hand, foot, and eye, we found a significant difference only in terms of the dominance of the eye. In 44 (41.9%) of the patients, we found dominance of the left eye. In patients with resistance, the percentage established by us is higher-at 26 (57.8%). These results indicate that the increased percentage of mixed dominance in patients with schizophrenia is mainly due to left-sided lateralization of the eye, especially in those with resistance to treatment. Conclusion: We find an increased number of patients with cross-dominance left eye dominance in patients with schizophrenia. Cross-dominance and left eye dominance are associated with a higher probability of symptom resistance than other forms of lateralization (left-handed or right-handed). The high percentage of cross-dominance is due to the high percentage of left-sided dominance of the eye.

Early Markers in Resistant Schizophrenia: Effect of the First Antipsychotic Drug.

BACKGROUND: Schizophrenia is a mental illness with a multifactorial etiology and clinical presentation. Treatment is mainly with antipsychotic drugs. Despite the increasing number of antipsychotic drugs, there has been no significant change in the percentage of resistant cases. These data gave us reason to look for a link between the effect of the first individually selected antipsychotic drug and the established resistance to therapy. METHOD: An assessment has been made of 105 patients with chronic schizophrenia with consecutive psychotic episodes. The choice of antipsychotic has been made on the basis of clinical features, history of efficacy of previously used neuroleptics, anthropometric features, as well as somatic comorbidities. Accidental use of benzodiazepines in anxiety conditions as well as correctors in indications for extrapyramidal problems have been reported. Assessment was made based on clinical observation as well as on changes in PANSS score. RESULTS: Of the 105 observed patients, the effectiveness of the first antipsychotic effect was found in 46.7% of patients. Follow-up of patients for a period of 12 weeks revealed that 45 (42.8%) of them had resistant schizophrenia, while the remaining 60 (57.2%) achieved clinical remission and initial functional recovery. The effect of the first antipsychotic drug was established in 9 (20%) of the patients with resistant schizophrenia and in 40 (66.57%) of the patients in clinical remission. CONCLUSION: The evaluation of the first antipsychotic medication is significant for the prognosis of patients with schizophrenia. Its lack of effectiveness indicates a high probability of resistance and can be a good indicator of earlier change and a possible search for more "aggressive" measures to prevent future resistance and possible disability.

Dissociative Model in Patients With Resistant Schizophrenia.

BACKGROUND: Schizophrenia is a severe mental illness in which, despite the growing number of antipsychotics from 30 to 50% of patients remain resistant to treatment. Many resistance factors have been identified. Dissociation as a clinical phenomenon is associated with a loss of integrity between memories and perceptions of reality. Dissociative symptoms have also been found in patients with schizophrenia of varying severity. The established dispersion of the degree of dissociation in patients with schizophrenia gave us reason to look for the connection between the degree of dissociation and resistance to therapy. METHODS: The type of study is correlation analysis. 106 patients with schizophrenia were evaluated. Of these, 45 with resistant schizophrenia and 60 with clinical remission. The Positive and Negative Syndrome Scale (PANSS) and Brief Psychiatric Rating Scale (BPRS) scales were used to assess clinical symptoms. The assessment of dissociative symptoms was made with the scale for dissociative experiences (DES). Statistical methods were used to analyze the differences in results between the two groups of patients. RESULTS: Patients with resistant schizophrenia have a higher level of dissociation than patients in remission. This difference is significant and demonstrative with more than twice the level of dissociation in patients with resistant schizophrenia.The level of dissociation measured in patients with resistant schizophrenia is as high as the points on the DES in dissociative personality disorder. CONCLUSION: Patients with resistant schizophrenia have a much higher level of dissociation than patients in clinical remission. The established difference between the two groups support to assume that resistance to the administered antipsychotics is associated with the presence of high dissociation in the group of resistant patients. These results give us explanation to think about therapeutic options outside the field of antipsychotic drugs as well as to consider different strategies earlier in the diagnostic process.

A girl with tuberous sclerosis complex presenting with severe epilepsy and electrical status epilepticus during sleep, and with high-functioning autism and mutism.

Most patients with tuberous sclerosis complex (TSC) suffer from epilepsy, and many have cognitive and behavioral problems like severe intellectual disability, autism, and hyperactivity. Only rare patients with TSC and autism have a normal intelligence quotient. We report a 13-year-old girl with definite TSC who had early-onset severe epilepsy, autistic behavior, and moderate developmental delay. By school age, however, she had normal intelligence; her intelligence quotient was at least 70 based on a Stanford-Binet test that she refused to complete. She showed good reading, writing, and language comprehension skills, and the special abilities of hyperlexia, hypermnesia, and hypercalculia. However, she did not speak. Criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, and her Childhood Autism Rating Scale score of 36 indicated mild to moderate autism. She had severe electroencephalographic abnormalities: hypsarrhythmia, multifocal or generalized epileptiform discharges, and electrical status epilepticus during sleep, with a continuous left temporal focus. Magnetic resonance imaging showed many cortical tubers in all brain lobes, and subependymal nodules. We discuss possible explanations for her lack of speech. Considered as speech apraxia, her mutism could be either a symptom of her TSC or a component of her autism. Another possibility is that long-lasting electrical status epilepticus during sleep led to her autistic behavior and language arrest. Still another possibility is that a disinhibited mammalian target of rapamycin (mTOR) pathway was at the root of all of her neuropsychiatric symptoms.