The association between reasons for first using cannabis, later pattern of use, and risk of first-episode psychosis: the EU-GEI case-control study.

BACKGROUND: While cannabis use is a well-established risk factor for psychosis, little is known about any association between reasons for first using cannabis (RFUC) and later patterns of use and risk of psychosis. METHODS: We used data from 11 sites of the multicentre European Gene-Environment Interaction (EU-GEI) case-control study. 558 first-episode psychosis patients (FEPp) and 567 population controls who had used cannabis and reported their RFUC.We ran logistic regressions to examine whether RFUC were associated with first-episode psychosis (FEP) case-control status. Path analysis then examined the relationship between RFUC, subsequent patterns of cannabis use, and case-control status. RESULTS: Controls (86.1%) and FEPp (75.63%) were most likely to report 'because of friends' as their most common RFUC. However, 20.1% of FEPp compared to 5.8% of controls reported: 'to feel better' as their RFUC (χ2 = 50.97; p < 0.001). RFUC 'to feel better' was associated with being a FEPp (OR 1.74; 95% CI 1.03-2.95) while RFUC 'with friends' was associated with being a control (OR 0.56; 95% CI 0.37-0.83). The path model indicated an association between RFUC 'to feel better' with heavy cannabis use and with FEPp-control status. CONCLUSIONS: Both FEPp and controls usually started using cannabis with their friends, but more patients than controls had begun to use 'to feel better'. People who reported their reason for first using cannabis to 'feel better' were more likely to progress to heavy use and develop a psychotic disorder than those reporting 'because of friends'.

Kikuchi-Fujimoto disease - a case report of a paediatric patient.

Kikuchi-Fujimoto disease is usually a self-limited cause of lymphadenitis. It is a prevalent disease amongst Asian individuals, but rare in other parts of the world. It affects especially young women, with limited cases described in children. Kikuchi-Fujimoto disease is characterized by focal and tender lymphadenopathy, mostly cervical, accompanied by fever and, less commonly, systemic manifestations. This disease is seldom associated with systemic lupus erythematosus. Herein we describe the case of a previously healthy 7-year-old male patient, who presented with prolonged fever, rash, polyarthritis, cervical lymphadenopathy, hepatosplenomegaly, leucocytosis and markedly elevated inflammatory markers. No changes were seen on the echocardiogram. Antinuclear antibodies were not identified and complement levels were normal. Differential diagnosis included systemic juvenile idiopathic arthritis, infectious diseases and malignancy. Bone marrow aspiration and biopsy were normal. The cervical node biopsy was diagnostic for Kikuchi-Fujimoto disease. Oral corticosteroids were started with notorious clinical response. After one year of follow up, the patient is without medication and remains asymptomatic. This case report shows the often-convoluted course of Kikuchi-Fujimoto disease and diagnostic dilemmas clinicians face when dealing with atypical presentations.

Impact of previous tobacco use with or without cannabis on first psychotic experiences in patients with first-episode psychosis.

OBJECTIVE: There is high prevalence of cigarette smoking in individuals with first-episode psychosis (FEP) prior to psychosis onset. The purpose of the study was to determine the impact of previous tobacco use with or without cannabis on first psychotic experiences in FEP and the impact of this use on age of onset of symptoms, including prodromes. METHODS: Retrospective analyses from the naturalistic, longitudinal, multicentre, "Phenotype-Genotype and Environmental Interaction. Application of a Predictive Model in First Psychotic Episodes (PEPs)" Study. The authors analysed sociodemographic/clinical data of 284 FEP patients and 231 matched healthy controls, and evaluated first psychotic experiences of patients using the Symptom Onset in Schizophrenia Inventory. RESULTS: FEP patients had significantly higher prevalence of tobacco, cannabis, and cocaine use than controls. The FEP group with tobacco use only prior to onset (N = 56) had more sleep disturbances (42.9% vs 18.8%, P = 0.003) and lower prevalence of negative symptoms, specifically social withdrawal (33.9% vs 58%, P = 0.007) than FEP with no substance use (N = 70), as well as lower prevalence of ideas of reference (80.4% vs 92.4%, P = 0.015), perceptual abnormalities (46.4% vs 67.4%, P = 0.006), hallucinations (55.4% vs 71.5%, P = 0.029), and disorganised thinking (41.1% vs 61.1%, P = 0.010) than FEP group with previous tobacco and cannabis use (N = 144). FEP patients with cannabis and tobacco use had lower age at first prodromal or psychotic symptom (mean = 23.73 years [SD = 5.09]) versus those with tobacco use only (mean = 26.21 [SD = 4.80]) (P = 0.011). CONCLUSIONS: The use of tobacco alone was not related to earlier age of onset of a first psychotic experience, but the clinical profile of FEP patients is different depending on previous tobacco use with or without cannabis.

Intra-individual variation of clozapine and norclozapine plasma levels in clinical practice. / Variación intraindividual en los niveles plasmáticos de clozapina y norclozapina en la práctica clínica.

INTRODUCTION: Clozapine plasma levels are useful to monitor drug compliance, and also to assess and to prevent some side effects. Recently, routine monitoring to all clozapine-treated patients has been proposed to prevent relapses. However, high intra-individual variability in plasma levels has been reported too, although these studies have some limitations. METHODS: We analysed differences between 2clozapine plasma levels separated by at least one year in a subgroup of 28 outpatients (82% male, mean age 47.9 years-old) with diagnosis of non-affective psychosis in clinical remission whose clozapine doses and smoking habits remained unchanged. RESULTS: We found a non-significant increase in clozapine plasma levels [.30mg/L (SD=.14) vs. .32 (SD=.17); t=-.858, p=.40] and a significant decrease in norclozapine plasma levels [.27 (SD=.11) vs. .22 (SD=.10); t=3.27; p=.003]. Absolute coefficient of variation (CV) between first and second assessment were calculated. Forty-six and fifty-seven percent of cases had CV 20% in clozapine and norclozapine, respectively. CV of 50% was seen in 20.7% and 13.8% of clozapine and norclozapine test respectively. We discussed potential causes of such high CV. CONCLUSIONS: Our study suggest high intra-individual variation even in a subgroup of very stable patients, which suggest that routine monitoring of these levels may be indicated in order to detect significant plasma variations. We think that clinicians should act with caution in case of a sudden decrease in plasma level. In the absence of obvious symptom severity variation, sources of intra-individual fluctuations might be considered first, before assuming poor compliance.

Fibrosis: a distinguishing feature in the pathology of neural leprosy.

BACKGROUND: Fibrosis in the peripheral nerve is the end stage of leprous neuropathy and the cause of the resulting permanent neural function impairments. Preventive measures to avoid this irreversible pathological state are a relief strategy for leprosy sufferers. OBJECTIVES: The present study describes the frequency of fibrosis along with its characterisation and pathogenic development. METHODS: Six-hundred-and-thirteen nerve samples were sorted from 278 neural leprosy (NL) and 335 non-leprosy neuropathy patients (ON). The total number of samples was histologically examined by routine staining methods (haematoxylin-eosin, Wade staining and Gomori's trichrome) and fibrosis was evaluated via semi-quantitative estimation. FINDINGS: Fibrosis was most frequent in the NL group (33% against 0.4% in ON) while fibrosis in association with endoneurial microfasciculation was found in 38 (41.3%) of the NL samples in the examination of semithin sections. Pericytic activation in the perivascular environment was confirmed to be the source of the fibroblasts and perineurial cells delimiting microfascicles. End-stage fibrosis in leprosy displays an arrangement of microfascicles devoid of neural components (i.e., Schwann cells and axons) lined by an intermediate phenotype of fibroblastic-perineurial cells filled with bundles of collagen fibres. MAIN CONCLUSIONS: The present study underscores that fibrosis is frequently the severe end stage of neural leprosy NL pathogeny after analysing the notably distinct development of fibrosis within the neural environment.

Gene-environment interaction between an endocannabinoid system genetic polymorphism and cannabis use in first episode of psychosis.

Alterations of the endocannabinoid system (ECS) may play an important role in the development of schizophrenia and other psychotic disorders. Cannabis use is one of the environmental factors more repeatedly related to an increase the risk of developing a psychotic episode, while its use modifies the ECS normal function. In the present study we purposed to examine the gene by environment (GxE) interaction between 15 selected single nucleotide polymorphisms (SNPs) related to the ECS and cannabis use in a cohort of 321 patients with a first episode of psychosis (FEP) and 241 matched healthy controls. We found the fatty-acid amide hydrolase (FAAH) rs2295633 SNP genetic polymorphism was associated with a greater risk of presenting a FEP in subjects with relevant cannabis use, but not in subjects without a history of cannabis use. The probability of presenting a FEP was tenfold higher (OR: 10.69) in cannabis users who were homozygote carriers of the T allele of the FAAH rs2295633 SNP, compared to users of cannabis without this genotype. We also found that a higher a proportion of TT carriers of the FAAH rs2295633 SNP with a positive history of cannabis use was treated with high potency antipsychotic. This study has identified a GxE-environment interaction between a genetic polymorphism from the ECS and cannabis use involved in the risk of presenting a FEP. Although this preliminary data should be replicated with independent samples, our results highlight the importance of the pro-psychotic effects of exogenous cannabis use over the ECS in certain subjects.

Gastric mixed adenoneuroendocrine carcinoma case report.

Mixed adenoneuroendocrine carcinomas are rare tumors that contain both an exocrine and an endocrine component. Since the latest classification by the World Health Organization and with the aid of immunostaining, more mixed adenoneuroendocrine carcinomas are now identified and diagnosed. Nonetheless, our knowledge of these tumors is still limited, notably concerning gastric variants, as the cases reported in the literature are very limited. The clinical and surgical treatment, including the chemotherapy schemes, the prognosis, and recurrence still represent challenges for the medical teams. We present the case of a 62-year-old woman. After an upper endoscopy revealed multiple polyps and a low-grade neuroendocrine tumor, a D2 radical gastrectomy was performed. A low output esophageal anastomotic leak was discovered in the postoperative period and successfully managed. Pathology revealed a gastric mixed adenoneuroendocrine carcinoma, the first case of this kind reported in Ecuador. Patient is doing well and under constant surveillance up until her 13th postoperative month.

Fibrosis: a distinguishing feature in the pathology of neural leprosy

BACKGROUND Fibrosis in the peripheral nerve is the end stage of leprous neuropathy and the cause of the resulting permanent neural function impairments. Preventive measures to avoid this irreversible pathological state are a relief strategy for leprosy sufferers. OBJECTIVES The present study describes the frequency of fibrosis along with its characterisation and pathogenic development. METHODS Six-hundred-and-thirteen nerve samples were sorted from 278 neural leprosy (NL) and 335 non-leprosy neuropathy patients (ON). The total number of samples was histologically examined by routine staining methods (haematoxylin-eosin, Wade staining and Gomori's trichrome) and fibrosis was evaluated via semi-quantitative estimation. FINDINGS Fibrosis was most frequent in the NL group (33% against 0.4% in ON) while fibrosis in association with endoneurial microfasciculation was found in 38 (41.3%) of the NL samples in the examination of semithin sections. Pericytic activation in the perivascular environment was confirmed to be the source of the fibroblasts and perineurial cells delimiting microfascicles. End-stage fibrosis in leprosy displays an arrangement of microfascicles devoid of neural components (i.e., Schwann cells and axons) lined by an intermediate phenotype of fibroblastic-perineurial cells filled with bundles of collagen fibres. MAIN CONCLUSIONS The present study underscores that fibrosis is frequently the severe end stage of neural leprosy NL pathogeny after analysing the notably distinct development of fibrosis within the neural environment.

Wilkie's syndrome, a missed opportunity.

Wilkie's syndrome is a rare cause of duodenal obstruction that can easily be missed at clinical practice. It is characterized by nausea, abdominal pain and vomit. It usually affects young adults, and it's caused by a low aortomesenteric angle resulting in vascular compression of the duodenum. Symptoms could resemble many of the symptoms presented in a patient with a suspected eating disorder. The non-specificity of the clinical signs and symptoms can confuse, delay the diagnosis and expose the patient to potentially hazardous therapies. We report a case of a 20-year-old patient who presented to the emergency room with a history of intermittent vomiting and abdominal pain. He had been previously misdiagnosed with an eating disorder and received physiological therapy. Nonetheless, his pain persisted. After further evaluation with the use of imaging techniques, a low aortomesenteric angle was discovered. He underwent surgery and completely recovered. On follow up controls patient is well and he no longer had episodes of vomiting.

Relationship Between Antipsychotic Medications and Cerebrovascular Disease in Patients With Serious Mental Illness.

INTRODUCTION AND OBJECTIVES: Cerebrovascular disease (CVD), especially in its asymptomatic forms, is relatively common in patients with serious mental illness (SMI). Nevertheless, the literature on this topic is scarce and sometimes contradictory. Antipsychotic medications, especially atypical agents, play an important role in the overall cardiovascular health of these patients. The goal of this study was to analyze the frequency of CVD in patients with and without SMI. PATIENTS AND METHODS: This retrospective cohort study compared the frequency of CVD, including silent forms, in a group of patients without mental illness and without a history of taking antipsychotic medication, with another group of patients diagnosed with SMI who had received antipsychotic treatment. The 2 groups were matched for age and sex, and the mean age of the subjects in the 2 groups was 63 years. RESULTS: The frequency of CVD was the same in both groups and it was not modified by the use of antipsychotic medications. A nonsignificant trend toward an association between CVD and prolonged use of antipsychotic polypharmacy was found. CONCLUSIONS: In this study, in contrast to previous reports, use of antipsychotic medications and the presence of SMI were not associated with an increased risk of CVD.

Distinct risk factors for obsessive and compulsive symptoms in chronic schizophrenia.

BACKGROUND: Obsessive-compulsive disorder (OCD) is common in clozapine-treated patients although the actual prevalence, phenomenology and risk factors remain unclear. The aim of the present study was to address the three aforementioned questions. METHODS: The electronic records of a large cohort of clozapine-medicated schizophrenia patients routinely screened for OCD were used. The Obsessive Compulsive Inventory Revised version (OCI-R) was available from 118 cases and a 21 points cut-off threshold for OCD was defined. RESULTS: OCD prevalence was 47%, higher in patients on poly-pharmacy than on monotherapy (64% vs 31%; p = 0.001). Two OCI-R factors had significantly higher scores and distinct risk factors: checking behaviour (mean = 5.1; SD = 3.6) correlated with length of clozapine treatment (r = 0.21; p = 0.026), and obsessing factor (mean = 4.8; SD = 3.6) correlated with psychosis severity (r = 0.59; p = 0.001). These factors along with total OCI-R, did not correlate with either clozapine dose or plasma levels, after correcting for psychosis severity. CONCLUSIONS: Screening for OCD in clozapine patients, and probably in those treated with structurally similar drugs with potent antiserotoninergic properties, should be widely adopted by clinicians. Further research is needed to understand the pathophysiology underlying repetitive behavior onset in clozapine-treated patients.

The toxic nature of murine amylin and the immune responsivity of pancreatic islet to conformational antibody in mice.

The human amylin is a pancreatic peptide hormone found in hyperhormonemic state along with insulin in subclinical diabetes. Amylin has been associated with the pathology of type 2 diabetes, particularly due to its ability to assembly into toxic oligomers and amyloid specimens. On the other hand, some variants such as murine amylin has been described as non-amyloidogenic, either in vitro or in vivo. Recent data have demonstrated the amyloid propensity of murine amylin and the therapeutic analogue pramlintide, suggesting a universality for amylin amyloidosis. Here, we report the amyloidogenesis of murine amylin, which showed lower responsivity to the fluorescent probe thioflavin T compared to human amylin, but presented highly organized fibrilar amyloid material. The aggregation of murine amylin also resulted in the formation of cytotoxic specimens, as evaluated in vitro in INS-1 cells. The aggregation product from murine amylin was responsive to a specific antibody raised against amyloid oligomers, the A11 oligomer antibody. Pancreatic islets of wild-type Swiss male mice have also shown responsivity for the anti-oligomer, indicating the natural abundance of such specimen in rodents. These data provide for the first time evidences for the toxic nature of oligomeric assemblies of murine amylin and its existence in wild-type, non-transgenic mice.

Evolution of metabolic risk factors over a two-year period in a cohort of first episodes of psychosis.

Patients with a first episode of psychosis (FEP) display a broad range of metabolic risk factors related to the development of diverse medical comorbidities. Initial stages of these disorders are essential in understanding the increased vulnerability of developing cardiometabolic disturbances, associated with a reduced life expectancy. This study aimed to evaluate the metabolic profile of a cohort of patients with a FEP and its evolution during a two year follow-up, as well as the factors that influence the changes in their metabolic status. 16 participating centers from the PEPs Project recruited 335 subjects with a FEP and 253 matched healthy controls, aged 9-35years. We investigated a set of anthropometric measures, vital signs and laboratory data obtained from each participant over two years in a prospective, naturalistic study. From the beginning of the study the FEP group showed differences in the metabolic profile compared to the control group, together with a progressive worsening in the major part of the analyzed variables during the follow-up period, with higher rates of obesity and metabolic syndrome. Certain risk factors were related to determinate clinical variables such as male gender, the presence of affective symptoms or an early onset or to treatment variables such as the use of antipsychotic polypharmacy, antidepressants or mood stabilizers. Our results highlight the extremely high risk of patients at early phases of schizophrenia and other psychotic disorders of developing cardiovascular comorbidity and the fast worsening of the metabolic profile during the first two years.

Cannabis use, COMT, BDNF and age at first-episode psychosis.

Although an interaction between COMT Val158Met and BDNF Val66Met polymorphisms with cannabis use has been proposed with respect to the risk of psychosis emergence, findings remain inconclusive. The aim of the present study was to evaluate the different possible associations between these polymorphisms and early cannabis use and the age at the first episode of psychosis. The relationship between age at psychosis onset and COMT Val158Met and BDNF Val66Met polymorphisms with early cannabis use as well as those factors associated with early cannabis use were investigated. Among 260 Caucasian first-episode psychosis patients, early cannabis use and the presence of the met-allele from the BDNF Val66Met polymorphism were significantly associated with age at psychosis onset. Furthermore, early cannabis use was significantly associated with male gender in the logistic regression analysis. These findings provide evidence of the important role of early cannabis use and the Val66Met BDNF polymorphism on age at psychosis onset and they point out to sex-specific differences in cannabis use patterns.

Spanish consensus on the risks and detection of antipsychotic drug-related hyperprolactinaemia. / Consenso español sobre los riesgos y detección de la hiperprolactinemia iatrogénica por antipsicóticos.

INTRODUCTION: Iatrogenic hyperprolactinaemia (IHPRL) has been more frequently related to some antipsychotic drugs that provoke an intense blockade of dopamine D2 receptors. There is a wide variation in clinical practice, and perhaps some more awareness between clinicians is needed. Due to the high frequency of chronic treatment in severe mental patients, careful attention is recommended on the physical risk. IHPRL symptoms could be underestimated without routine examination. METHODOLOGY: An intense scientific literature search was performed in order to draw up a multidisciplinary consensus, including different specialists of psychiatry, endocrinology, oncology and internal medicine, and looking for a consensus about clinical risk and detection of IHPRL following evidence-based medicine criteria levels (EBM I- IV). RESULTS: Short-term symptoms include amenorrhea, galactorrhoea, and sexual dysfunction with decrease of libido and erectile difficulties related to hypogonadism. Medium and long-term symptoms related to oestrogens are observed, including a decrease bone mass density, hypogonadism, early menopause, some types of cancer risk increase (breast and endometrial), cardiovascular risk increase, immune system disorders, lipids, and cognitive dysfunction. Prolactin level, gonadal hormones and vitamin D should be checked in all patients receiving antipsychotics at baseline although early symptoms (amenorrhea-galactorrhoea) may not be observed due to the risk of underestimating other delayed symptoms that may appear in the medium term. Routine examination of sexual dysfunction is recommended due to possible poor patient tolerance and low compliance. Special care is required in children and adolescents, as well as patients with PRL levels >50ng/ml (moderate hyperprolactinaemia). A possible prolactinoma should be investigated in patients with PRL levels >150ng/ml, with special attention to patients with breast/endometrial cancer history. Densitometry should be prescribed for males >50 years old, amenorrhea>6 months, or early menopause to avoid fracture risk.

Risk factor assessment and counselling for 12 months reduces metabolic and cardiovascular risk in overweight or obese patients with schizophrenia spectrum disorders: The CRESSOB study.

BACKGROUND: Metabolic syndrome (MS) and cardiovascular risk factors (CRF) have been associated with patients with schizophrenia. The main objective is to assess the evolution of CRF and prevalence of MS for 12 months in a cohort of overweight patients diagnosed with schizophrenia schizophreniform disorder or schizoaffective disorder in which the recommendations for the assessment and control of metabolic and cardiovascular risk were applied. METHODS: The Control of Metabolic and Cardiovascular Risk in Patients with Schizophrenia and Overweight (CRESSOB) study is a 12-month, observational, prospective, open-label, multicentre, naturalistic study including 109 community mental health clinics of Spain. The study included a total of 403 patients, of whom we could collect all variables related to CRF and MS in 366 patients. Of these 366 patients, 286 completed the follow-up, (baseline, months 3, 6 and 12) where they underwent a complete physical examination and a blood test (glucose, cholesterol and triglycerides), they were asked about their health-related habits (smoking, diet and exercise) and they were given a series of recommendations to prevent cardiovascular risk and MS. RESULTS: A total of 403 patients were included, 63% men, mean age (mean; (SD)) 40.5 (10.5) years. After 12 months, the study showed statistically significant decrease in weight (p<0.0001), waist circumference (p<0.0001), BMI (p<0.0001), blood glucose (p=0.0034), total cholesterol (p<0.0001), HDL cholesterol (p=0.02), LDL cholesterol (p=0.0023) and triglycerides (p=0.0005). There was a significant reduction in the percentage of smokers (p=0.0057) and in the risk of heart disease at 10 years (p=0.0353). CONCLUSION: Overweight patients with schizophrenia who receive appropriate medical care, including CRF monitoring and control of health-related habits experience improvements with regard to most CRFs.

A Pharmacovigilance Study in First Episode of Psychosis: Psychopharmacological Interventions and Safety Profiles in the PEPs Project.

BACKGROUND: The characterization of the first episode of psychosis and how it should be treated are principal issues in actual research. Realistic, naturalistic studies are necessary to represent the entire population of first episode of psychosis attended in daily practice. METHODS: Sixteen participating centers from the PEPs project recruited 335 first episode of psychosis patients, aged 7 to 35 years. This article describes and discusses the psychopharmacological interventions and safety profiles at baseline and during a 60-day pharmacovigilance period. RESULTS: The majority of first episode of psychosis patients received a second-generation antipsychotic (96.3%), orally (95%), and in adjusted doses according to the product specifications (87.2%). A total of 24% were receiving an antipsychotic polytherapy pattern at baseline, frequently associated with lower or higher doses of antipsychotics than the recommended ones. Eight patients were taking clozapine, all in monotherapy. Males received higher doses of antipsychotic (P=.043). A total of 5.2% of the patients were being treated with long-acting injectable antipsychotics; 12.2% of the patients received anticholinergic drugs, 12.2% antidepressants, and 13.7% mood stabilizers, while almost 40% received benzodiazepines; and 35.52% reported at least one adverse drug reaction during the pharmacovigilance period, more frequently associated with higher antipsychotic doses and antipsychotic polytherapy (85.2% vs 45.5%, P<.001). CONCLUSIONS: These data indicate that the overall pharmacologic prescription for treating a first episode of psychosis in Spain follows the clinical practice guideline recommendations, and, together with security issues, support future research of determinate pharmacological strategies for the treatment of early phases of psychosis, such as the role of clozapine, long-acting injectable antipsychotics, antipsychotic combination, and the use of benzodiazepines.

Long-term effectiveness of electroconvulsive therapy in adolescents with schizophrenia spectrum disorders.

To compare a sample of adolescents with schizophrenia spectrum disorders (SSD) treated with either ECT or antipsychotics (AP) alone at long-term follow-up. Patients diagnosed with SSD (n = 21) treated with ECT due to resistance to AP or catatonia under the age of 18 years (ECT group), were compared to a randomly selected group of patients with SSD treated only with AP (non-ECT group) (n = 21) and matched for age, gender, diagnosis and duration of illness. Baseline data were gathered retrospectively from medical records. Subjects were assessed at follow-up (mean of follow-up period = 5.5 years; range 2-9 years) using several clinical scales such as the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impression Scale (CGI) and the Global Assessment of Functioning (GAF). Improvement in PANSS positive, negative, general, total and CGI and GAF scores between baseline and follow-up assessment did not differ significantly between groups. At follow-up, no differences were observed for the PANSS negative, CGI and GAF scores between groups, but patients in the ECT group still had higher PANSS total, positive and general scores. ECT treatment followed by AP medication in treatment-resistant SSD or catatonia is at least as effective in the long term as AP alone in non-resistant patients.