Combining Three Long-acting Injectable Antipsychotics: A Case Series.

IntroductionSchizophrenia is often characterized by chronic progression and frequent relapses. However, recent evidence suggests that many patients can achieve symptoms remission and functional recovery through integrated pharmacological and psychosocial interventions. Despite treatment advances, up to 34% of patients are resistant to standard antipsychotic treatments, with clozapine being the gold standard for treatment-resistant schizophrenia (TRS). However, up to 60% of TRS patients may not respond adequately to clozapine due to its adverse effects and lack of compliance. Recently, the use of two long-acting injectable (LAI) antipsychotics has emerged as a potential strategy for managing TRS, particularly in patients with poor adherence to oral therapies.ObjectivesThe objective is to provide clinical insights into this novel pharmacological approach consisting in the administration of two LAI antipsychotics in patients with treatment resistant schizophrenia.MethodsThis case report describes the clinical management of a 62-year-old woman with a 20-year history of treatment-resistant paranoid schizophrenia, characterized by multiple hospitalizations, delusions, auditory hallucinations, disorganized behavior, and non-adherence to oral medications.ResultsDue to the patient’s poor response to prior treatments, including clozapine, a novel therapeutic strategy was adopted during her hospitalization in March 2023. Two LAI antipsychotics, haloperidol decanoate (100 mg/28 days) and aripiprazole (400 mg/28 days), were administered alternately to optimize symptom control while minimizing adverse effects. Over 8 weeks, the patient demonstrated significant improvements in psychotic symptoms, mood, and functioning. Importantly, adherence to treatment improved.ConclusionsThis case highlights the potential efficacy and safety of combining two LAI antipsychotics in TRS patients, particularly those with poor adherence to oral therapies. The alternating administration of haloperidol and aripiprazole may exploit the synergistic effects of first- and second-generation antipsychotics, offering a promising alternative for managing complex cases of schizophrenia. Further studies are needed to confirm these findings and establish guidelines for dual LAI use in TRS patients.Disclosure of InterestNone Declared

How Would You Like to Take Your Medicine 2 Times a Year? Paliperidone Palmitate Every 6 Months for the Maintenance Treatment of Schizophrenia

BackgroundPharmacological, neurochemical and electrophysiological studies provide compelling evidence that N-methyl-D-aspartate-receptor (NMDAR) hypofunction is a pathologic feature of schizophrenia (SZ). GWAS studies highlighted risk genes such as Serine Racemase (SRR), which synthesizes D-Serine (D-Ser), the co-agonist of glycine site at NMDARs, and Serine Hydroxymethyltransferase (SHMT1) which synthesizes L-Serine (L-Ser), the substrate of SRR. Around 30% of patients do not respond to dopamine modulation and are considered to suffer from treatment resistant SZ (TRS). While the exact cause of TRS remains unclear, multiple lines of evidence suggest the involvement of a dysregulation of the Glutamate (Glu) neurotransmission. To test the hypothesis whether Glu system dysregulation mediated by NMDAR hypofunction is an underlying mechanism of TRS, we investigate the Glu and D-Ser pathways in TRS and treatment responder (RESP) early psychosis patients (EPP).MethodsFrom a total of 621 EPP aged 18 to 35, included in the TIPP (early Intervention Program in Lausanne, Baumann & al., 2013), 225 EPP were classified as TRS (n=33) or RESP (n=192) according to the strict Treatment Response and Resistance in Psychosis (TRRIP) criteria (Howes & al., 2017), with compliance ascertained by antipsychotic plasma levels. A matched healthy control (HC) group (N=114) was also recruited (DIGS criteria). No patient was taking clozapine at baseline. Clinical data was collected over a 3-year period. At baseline, following systems were assessed: 1) D-Ser pathway: plasmatic D-Ser, L-Ser and Glycine by HPLC (Hashimoto & al., 2016), protein levels of SRR and SHMT1 by ELISA; 2) Glu pathway: Glu and glutamine in plasma (HPLC) and prefrontal cortex (magnetic resonance spectroscopy, Xin & al., 2016).ResultsD-Ser pathway: in TRS, SRR levels were decreased by 56% as compared to RESP. Interestingly, we observed a positive correlation between plasma levels of D-Ser (SRR metabolite) and L-Ser (SRR substrate) in the TRS (r= 0.58; p =0.0015) but not in the RESP group, suggesting that SRR dysregulation might be a limiting factor in TRS patients. Moreover, in TRS patients, SHMT1 levels were decreased by 15% as compared to RESP, with a positive correlation between the substrate and metabolite of SHMT1, glycine and L-Ser (r =0.48; p =0.011). Dysregulation of SHMT1 might thus be a limiting factor in the TRS group. As compared to HC, L-Ser and D-Ser were significantly increased in patients (p <0.001 for L-Ser, p =0.0001 for D-Ser). However, no difference was observed in D-Ser, L-Ser and glycine in TRS as compared to RESP, although L-Ser tended to be higher in male TRS patients (p =0.06).Glu pathway: comparing TRS with RESP patients, plasma Glu levels were increased in the TRS group (p <0.0001), whereas they were higher in both patient groups compared to HC (p <0.0001). Interestingly, plasma and brain Glu levels showed a negative correlation in EPP, mostly driven by RESP (r = -0.42; p =0.035), a correlation which was absent in HC.Global Assessment of Functioning (GAF): at baseline, TRS and RESP displayed the same range of GAF. After a 3-year follow-up, TRS patients had poorer functioning as compared to RESP group (p <0.0001).DiscussionTaken together, our results suggest that the TRS group, in which the levels of SRR and SHMT1 were lower and Glu plasma levels were higher, display a different regulation of the synthesis, degradation and/or accumulation of D-Ser and Glu as compared to the RESP group. However, replication in larger groups is needed. Moreover, our findings highlighted a dysregulation of D-Ser and Glu pathways in TRS patients in their early phase of psychosis. On the clinical side, our results confirm the significantly poorer functioning outcome in TRS patients.

Disease relapse, all-cause mortality, and adverse events associated with long-acting injectable antipsychotics versus oral antipsychotics in older people with schizophrenia in Hong Kong: a population-based within-subject analysis.

The corpus callosum (CC) is critical for inter-hemispheric integration, and its structural abnormalities have been implicated in the neurobiology of schizophrenia (SCZ). Approximately 20-35% of SCZ patients exhibit resistance to antipsychotics and are classified as treatment-resistant schizophrenia (TRS). To date, no studies have specifically analyzed CC morphology in TRS compared to healthy controls (HCs) and treatment-responsive SCZ patients (non-TRS). The study included 75 HCs and 97 SCZ patients (39 TRS and 58 non-TRS, including cannabis users and non-users). Participants underwent cross-sectional assessment using the Neurological Evaluation Scale (NES), the Brief Assessment of Cognition in Schizophrenia, and the Positive and Negative Syndrome Scale (PANSS). CC volume was measured via MRI and analyzed with a novel artificial intelligence program (MRI-AI) for single-subject assessment, with findings confirmed through group-level voxel-based morphometry (VBM). TRS patients exhibited significantly higher total PANSS (p < 0.001) and NES (p < 0.001) scores and performed worse on working memory tasks compared to non-TRS patients. MRI-AI identified CC volume reduction in 55.88% of TRS patients (TRS CC: 3.02 mL vs. non-TRS with cannabis use: 3.69 mL; without cannabis use: 3.28 mL; p = 0.002). VBM confirmed significant CC volume reduction in TRS patients relative to HCs (p = 0.004). Cannabis use in non-TRS patients did not significantly affect CC volume or cognitive performance. TRS is associated with pronounced neurological, cognitive, and clinical dysfunctions. Aberrant CC volume may contribute to TRS pathogenesis and executive function deficits. MRI-AI provides a robust, single-subject approach for characterizing CC abnormalities in schizophrenia, offering potential for personalized clinical assessment.

BackgroundSchizophrenia is a disabling psychiatric disease with a lifetime prevalence of 1%, which usually starts in late adolescence or initial adulthood and has a rare possibility of recovery. According to the extent of antipsychotic response, schizophrenia individuals can be divided into treatment resistant schizophrenia (TRS) and Treatment responders (non-TRS). Currently, it is unclear whether these categories belong to different biological and prognostic groups. Therefore, in order to deepen the knowledge of these conditions, we analyzed the cerebral metabolism of a sample of stabilized but still actively symptomatic TRS and non-TRS patients with substantial cognitive deficits.MethodsWe recruited 35 schizophrenia patients (18 TRS and 17 non-TRS) among approximately 80 consecutive non-affective psychotic patients, that were referred to our academic outpatient unit for supposed resistance to antipsychotics. The diagnosis of TRS was made by a structured diagnostic flowchart, according to published guidelines. Patients underwent a wide set of clinical and cognitive evaluations by trained raters. All patients who exhibited substantial cognitive deficits (at least two BACS/MATRICS items < than 1 - adjusted scores) and met inclusion/not met exclusion criteria were included in the neuroimaging study by 18F-fluorodeoxyglucose PET scans and structural 3T Magnetic Resonance Imaging. There were no statistically significant differences in age, chlorpromazine equivalents, and duration of illness between the TRS/non-TRS groups. Patients groups were matched with a control group. PET images were normalized on SPM template and then examined in visual and voxel-based analyses.ResultsGlobally, the visual analysis of the images showed a diffuse relative metabolic reduction in the cerebral cortex with prevalent frontal involvement in the majority of the patients of the TRS group and to a lesser extent in the non-TRS group. The voxel-per-voxel analysis revealed an extensive cluster of significant relative metabolic reduction in TRS patients compared to controls and to non-TRS patients (13653 voxels) localized bilaterally in the frontal cortex with a mild left prevalence. In particular, the metabolic reduction peaks involved the upper right and left medial frontal girder (BA6 and BA8, respectively), left opercular frontal (BA44), middle frontal girth (BA10) bilaterally, left lower frontal girth (BA47). Notably, at least three patients from the TRS group were excluded from the initial pool due to the observation of previously unrecognized structural brain anomalies.DiscussionIn this study, we observed that TRS patients had a relative hypometabolic state in dorsal and medial prefrontal cortex, including frontobasal areas, compared to controls and to non-TRS patients, while the striatum and the occipital cortex appeared relatively preserved. In non-TRS patients, brain distribution of 18F-FDG was more homogeneous and only slightly reduced in the cerebral cortex, as compared to controls.These patterns of brain metabolism cannot be associated with more severe cognitive dysfunctions in TRS patients since all patients included in the study had substantial cognitive impairments, irrespective of being TRS or non-TRS. Although it cannot be excluded that these differential patterns may stem from the lack of response to antipsychotics, our findings suggest distinct neurobiological alterations in TRS vs. non-TRS patients, which may include more relevant brain disconnections in non-responder ones.

Clinical evaluation of functional capacity in treatment resistant schizophrenia patients: Comparison and differences with non-resistant schizophrenia patients

Tobacco smoking is common in schizophrenia patients. It has been reported that schizophrenia patients who are tobacco smokers have better cognitive performances compared to those who are nonsmokers. However, little is known on the effects of tobacco smoking in treatment-resistant schizophrenia (TRS) patients. The aim of this study was to compare cognitive performances, psychotic symptoms, and social adjustment in tobacco smoker TRS patients compared to nonsmoker TRS patients. Smoker and nonsmoker TRS patients did not differ in demographics and in mean daily antipsychotic dose. Smoker TRS patients had significantly higher scores than nonsmoker patients on the positive and negative syndrome scale (PANSS) and on the negative symptoms subscale. These patients also performed worse than nonsmoker patients on problem-solving cognitive domain. Social adjustment was not significantly different between the two groups. In both groups of patients, worse cognitive performances were mostly predicted by higher severity of negative symptoms. Worse performances on the verbal memory and problem-solving cognitive domains were correlated with social-functioning impairment in tobacco smoker TRS patients but not in nonsmoker ones. The results showed that tobacco smoking was not significantly associated with better cognitive performances in TRS patients, while it was significantly associated with higher negative symptoms. Even if a direct causative mechanism cannot be inferred and despite the fact that these patients may use tobacco to self-medicate, it could be speculated that these associations may, at least partially, be related to a tobacco-smoking–induced worsening of abnormal dopamine dysfunction, which has been suggested to occur in TRS patients.

Schizophrenia is a chronic, debilitating psychiatric disorder with a high risk of relapse. Nonadherence to medication is a significant contributor to poor outcomes. Although long-acting injectable (LAI) antipsychotics prevent the relapse of schizophrenia, several factors present obstacles to the use of LAI antipsychotics, and clinical guidelines for LAI antipsychotics remain limited. To provide clinical recommendations, the Taiwanese Society of Biological Psychiatry and Neuropsychopharmacology (TSBPN) developed consensus statements for the effectiveness, target populations, initiation timing, and particular clinical situations for the use of LAI antipsychotics in patients with schizophrenia. After a systematic literature review, a working group drafted consensus statements for the selected clinical topics and determined the levels of evidence-based recommendation based on the latest World Federation of Societies of Biological Psychiatry grading system. A scientific committee evaluated the draft statements and decided the final recommendations regarding the grades by anonymous voting after incorporating clinical experience and practice into the evidence from research. The TSBPN proposed ten consensus statements for the application of LAI antipsychotics. The current evidence supported that LAI antipsychotics could be a treatment option for all schizophrenia patients, including first-episode patients. LAI antipsychotics could be initiated both during an acute psychotic episode and when patients are stable. The consensus also gave recommendations for particular clinical situations with insufficient scientific data, such as for use in elderly or adolescent patients, patients with treatment-resistant schizophrenia, and breakthrough psychosis, and strategies to assist patients/caregivers with decision making. The consensus statements developed by the TSBPN provide evidence-based clinical recommendations and could give clinicians more confidence when prescribing LAI antipsychotics to treat schizophrenia, thereby improving treatment outcomes.

BackgroundResistance to treatment affects up to 30% of patients with schizophrenia (SCZ). Current criteria for treatment-resistant schizophrenia (TRS) require failure to respond to two antipsychotic trials for adequate dose and duration. Clozapine is the only antipsychotic that is more effective to treatment resistant patients. Increasing evidence suggest that TRS may represent a subgroup of patients with distinct biological signature. Brain dysconnectivity was proposed as a major feature of schizophrenia and more intense in TRS patients. Earlier identification of TRS may anticipate the clozapine trial and, thus, reduce disability and treatment costs. In our study, we investigated whether there were differences in white matter integrity among first episode of psychosis (FEP), treatment-resistant schizophrenia (TRS), and non treatment-resistant schizophrenia (NTRS) patients.MethodsDiffusion-tensor brain MRI images were obtained for 34 TRS (19 males), 50 NTRS (26 males) and 35 FEP individuals (18 males), on a Siemens 1.5T MRI scanner. Treatment resistance was defined as persistence of moderate to severe symptoms, after failure to respond to 4–6 week trials of at least two different antipsychotic medications in adequate doses (equivalent to at least 400 mg/day of chlorpromazine or 5 mg/day of risperidone). All participants were receiving antipsychotic medication. All TRS patients were in clozapine use. Analysis of diffusion parameters was performed using a tract-based spatial statistics (TBSS), yielding a total two contrasts: i) mean FA is lower (or higher) in the TRS compared to the FEP, ii) mean FA is lower (or higher) in the NTRS compared to the FEP corrected for multiple comparisons using family-wise error (FWE) < 0.05. Gender and age were used as covariates.ResultsFEP patients were younger than TRS (mean±SD; 27.2 ± 7.93 y/o vs 37.06 y ±7.98 y/o;t=5.08, p <0.001) and NTRS (27.2 ± 7.93 y/o vs 37.71 y ±11.18 y/o; t=4.57, p<0.001) patients. Reduced in FA value was observed in the splenium of the corpus callosum (CC) in TRS patients when compared to FEP (47,598 voxels and thresholded at p<0.05). No differences between NTRS and FEP patients were observed.DiscussionOur results showed reduced FA value in the splenium of the CC in TRS when compared to FEP. The splenium of corpus callosum connects the temporal and occipital cortices, and have been previously associated with schizophrenia, but not specifically to treatment resistance in schizophrenia. Our data might suggest that patients with resistance to treatment have inefficiency in the connectivity of the white matter between these regions. Further studies will be required to replicate these findings and to explore the significance of white matter changes in the brain in order to determine if these are consequence of disease progression or related to clozapine exposure.

Network structure of psychotic symptoms and childhood trauma in first-episode versus treatment-resistant schizophrenia.

BackgroundInflammation has an important role in the pathogenesis of schizophrenia. The aim of this study was to investigate the levels of tumor necrosis factor (TNF) and matrix metalloproteinase-2 (MMP-2) in male patients with treatment-resistant schizophrenia (TRS) and chronic medicated schizophrenia (CMS), and the relationship with psychopathology.MethodsThe study enrolled 31 TRS and 49 cm male patients, and 53 healthy controls. Serum MMP-2 and TNF-α levels were measured by the Luminex liquid suspension chip detection method. Positive and Negative Syndrome Scale (PANSS) scores were used to evaluate symptom severity and Repeatable Battery for the Assessment of Neuropsychological Status was used to assess cognitive function.ResultsSerum TNF-α and MMP-2 levels differed significantly between TRS, CMS and healthy control patients (F = 4.289, P = 0.016; F = 4.682, P = 0.011, respectively). Bonferroni correction demonstrated that serum TNF-α levels were significantly elevated in CMS patients (P = 0.022) and MMP-2 levels were significantly higher in TRS patients (P = 0.014) compared to healthy controls. In TRS patients, TNF-α was negatively correlated with age (r=-0.435, P = 0.015) and age of onset (r=-0.409, P = 0.022). In CMS patients, MMP-2 and TNF-α were negatively correlated with PANSS negative and total scores, and TNF-α was negatively correlated with PANSS general psychopathology scores (all P < 0.05). MMP-2 levels were positively correlated with TNF-α levels (P < 0.05), but not with cognitive function (P > 0.05).ConclusionThe results indicate the involvement of inflammation in the etiology of TRS and CMS. Further studies are warranted.

P02-359 - Incidence rate and morphyology of cavum septum pellucidum in patients with treatment-resistant schizophrenia, major depression: A structural MRI study

When a patient presents with both psychotic and obsessive-compulsive symptoms, the clinician is faced with a differential diagnosis that includes comorbid schizophrenia and obsessive-compulsive disorder (OCD), OCD with poor insight, and schizophrenia with antipsychotic-induced obsessive-compulsive symptoms. If the psychotic symptoms are subthresh-old or attenuated in form, the individual may have OCD and putative prodromal schizophrenia. The authors present a case to outline a strategy for differentiating among these possible diagnoses and for optimizing treatment.

Three dysconnectivity patterns in treatment-resistant schizophrenia patients and their unaffected siblings