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AbstractBackgroundStudies that examine course and outcome in psychosis have reported considerable heterogeneity in terms of recovery, remission, employment, symptom presentation, social outcomes, and antipsychotic medication effects. Even with demonstrated heterogeneity in course and outcome, prophylactic antipsychotic maintenance therapy remains the prominent practice, particularly in participants with schizophrenia. Lack of efficacy in maintenance antipsychotic treatment and concerns over health detriments gives cause to re-examine guidelines.MethodsThis study was conducted as part of the Chicago follow-up study designed as a naturalistic prospective longitudinal research study to investigate the course, outcome, symptomatology, and effects of antipsychotic medication on recovery and rehospitalization in participants with serious mental illness disorders. A total of 139 participants with 734 observations were included in the analysis. GEE logistic models were applied to adjust for confounding factors measured at index hospitalization and follow-ups.ResultsOur data show that the majority of participants with schizophrenia or affective psychosis experience future episodes of psychosis at some point during the 20-year follow-up. There was a significant diagnostic difference between groups showing an increase in the number of future episodes of psychosis in participants with schizophrenia. Participants with schizophrenia not on antipsychotics after the first 2 years have better outcomes than participants prescribed antipsychotics. The adjusted odds ratio of not on antipsychotic medication was 5.989 (95% CI 3.588–9.993) for recovery and 0.134 (95% CI 0.070–0.259) for rehospitalization. That is, regardless of diagnosis, after the second year, the absence of antipsychotics predicted a higher probability of recovery and lower probability of rehospitalization at subsequent follow-ups after adjusting for confounders.ConclusionThis study reports multiple findings that bring into question the use of continuous antipsychotic medications, regardless of diagnosis. Even when the confound by indication for prescribing antipsychotic medication is controlled for, participants with schizophrenia and affective psychosis do better than their medicated cohorts, strongly confirming the importance of exposing the role of aiDSP and antipsychotic drug resistance.

The co-occurrence of delusions and other symptoms at the onset of psychosis is a challenge for theories about the aetiology of psychosis. This paper explores the relatedness of delusions about the experience of thinking (thought insertion, thought withdrawal, and thought broadcasting) and auditory verbal hallucinations by describing their trajectories over a 20-year period in individuals diagnosed with schizophrenia, affective and other psychosis, and unipolar depression nonpsychosis. The sample consisted of 407 participants who were recruited at index hospitalization and evaluated over six follow-ups over 20 years. The symptom structure associated with thought insertion included auditory verbal hallucinations, somatic hallucinations, other hallucinations, delusions of thought-dissemination, delusions of control, delusion of self-depreciation, depersonalization and anxiety. The symptom constellation of thought withdrawal included somatic hallucinations, other hallucinations, delusions of thought dissemination, delusions of control, sexual delusions, depersonalization, negative symptoms, depression, and anxiety. The symptom constellation of thought broadcasting included auditory verbal hallucinations, somatic hallucinations, delusions of thought-dissemination, delusion of self-depreciation, fantastic delusions, sexual delusions, and depersonalization. Auditory verbal hallucinations and delusions of self-depreciation were significantly associated with both thought insertion and thought broadcasting. Thought insertion and thought withdrawal were significantly associated with other hallucinations, delusions of control, and anxiety; thought withdrawal and thought broadcasting were significantly related to sexual delusions. We hypothesize that specific symptom constellations over time might be explained as the product of pseudo-coherent realities created to give meaning to the experience of the world and the self of individuals in psychosis based on both prior top-down and ongoing bottom-up elements.

Delusions are transdiagnostic and heterogeneous phenomena with varying degrees of intensity, stability, and dimensional attributes where the boundaries between everyday beliefs and delusional beliefs can be experienced as clearly demarcated, fuzzy, or indistinguishable. This highlights the difficulty in defining delusional realities. All individuals in the current study were evaluated at index and at least one of six subsequential follow-ups over 20 years in the Chicago Longitudinal Study. We assessed 16 distinct delusions categorized as thought or thematic delusions. We also examined the probability of recurrence and the relationships between delusions and hallucinations, depression, anxiety, and negative symptoms. The sample consisted of 262 individuals with schizophrenia vs. affective psychosis. Thought delusions were significantly different between groups at all follow-up evaluations except the 20-year timepoint. Thematic delusions were more common than thought delusions and show a significant decreasing pattern. In general, delusional content varied over time. Referential, persecutory, and thought dissemination delusions show the highest probability of recurrence. Hallucinations were the strongest indicator for thought, thematic, and overall delusions. The formation and maintenance of delusions were conceptualized as a multimodal construct consisting of sensory, perceptual, emotional, social, and somatic embodiment of an "experience of meanings". Given the significant associations between delusions and hallucinations, future work incorporating participatory research is needed to better define and align subjective and objective perspectives. Our research also points to the need for future clinical interventions that specifically evaluate and target the coexistence and entanglement of delusions and hallucinations.

thinking is a cognitive process that involves the assimilation of concepts reduced from diffuse sensory input, organized, and interpreted in a manner beyond the obvious. There are multiple facets by which abstraction is measured that include semantic, visual-spatial and social comprehension. This study examined the prevalence and course of abstract and concrete responses to semantic proverbs and aberrant abstraction (composite score of semantic, visual-spatial, and social comprehension) over 20 years in 352 participants diagnosed with schizophrenia, affective psychosis, and unipolar non-psychotic depression. We utilized linear models, two-way ANOVA and contrasts to compare groups and change over time. Linear models with Generalized Estimation Equation (GEE) to determine association. Our findings show that regardless of diagnosis, semantic proverb interpretation improves over time. Participants with schizophrenia give more concrete responses to proverbs when compared to affective psychosis and unipolar depressed without psychosis. We also show that the underlying structure of concretism encompasses increased conceptual overinclusion at index hospitalization and idiosyncratic associations at follow-up; whereas, abstract thinking overtime encompasses increased visual-spatial abstraction at index and rich associations with increased social comprehension scores at follow-up. Regardless of diagnosis, premorbid functioning, descriptive characteristics, and IQ were not associated with aberrant abstraction. Delusions are highly and positively related to aberrant abstraction scores, while hallucinations are mildly and positively related to this score. Lastly, our data point to the importance of examining the underlying interconnected structures of 'established' constructs vis-`a-vis mixed methods to provide a description of the rich interior world that may not always map onto current quantitative measures.

Both neurocognition and negative symptoms have demonstrated strong links to functional outcomes, such as work functioning, among those with severe mental illness (SMI). Prior models have suggested that reduced neurocognition 1) precedes or predicts greater negative symptoms and 2) indirectly influences functional outcomes via its impact on negative symptoms. The current study sought to also test a divergent model: whether greater negative symptoms predict reduced neurocognition and indirectly influence work functioning through their impact on neurocognition. Both models were tested using cross-sectional and prospective data spanning 20-years in a sample of 277 people with a SMI with psychotic features. Results showed that both models were supported in cross-sectional analyses. However, in prospective models predicting work functioning, only the models examining the indirect influence of negative symptoms on work functioning (7.5 to up to 20-years later) through neurocognition demonstrated significant mediation (i.e., a significant indirect effect); further, higher negative symptoms significantly predicted lower prospective neurocognition, while lower neurocognition did not significantly predict greater prospective negative symptoms. Although cross-sectional data were consistent with prior models, our prospective models offered greater support for a putative causal pathway running from negative symptoms to neurocognition-rather than the reverse-to work functioning. Findings have implications for mechanisms contributing to longitudinal work functioning and suggest that targeting negative symptoms prior to neurocognition could be more beneficial for long-term work outcomes.

Correll et al1 argue for a positive view of the risk-benefit ratio for long-term continuous antipsychotic treatment of schizophrenia. They claim that studies of long-term outcome which show negative results are not convincing because of confounding factors. Their chief argument is that in "non-randomized, uncontrolled studies… there is a high risk of confounding by indication and reverse causation, in that greater illness severity could be the cause of continued antipsychotic treatment, rather than being the effect"1. The other argument is that long-term continuous use of antipsychotics does not involve significant morbidity from dopamine supersensitivity psychosis. Here we provide evidence which severely questions both of these conclusions, showing that they overestimate the benefits and underestimate the risks of long-term antipsychotic treatment. There are at least eight studies assessing whether schizophrenia patients improve when treated longer than two-three years with antipsychotic medications. These studies have been conducted by eight different investigator groups. They include those by Wunderink et al in the Netherlands2, our own Chicago Followup Study3, the Suffolk County study of Kotov et al4 in the US, and the long-term data provided by the Danish OPUS trial5, the AESOP-10 study in England6, the Finnish Birth Cohort Study7, the Alberta Hospital Follow-Up Study in Western Canada8, and the international follow-up study by Harrison et al9. These research programs included samples studied from 7 to 20 years. Unlike short-term studies, none of them showed positive long-term results. Correll et al quote for support a study by Ran et al10 favoring long-term use of antipsychotics for schizophrenia in China. However, there are many weaknesses in that study. In particular, the untreated group was selected from much older unmarried chronic rural uneducated patients, while the treated group consisted of younger married educated urban patients, some of whom had received only one short period of medication over the 14 year period, rather than being continuously medicated. As we have noted, one argument used to explain the negative results of long-term antipsychotic treatment is that the schizophrenia patients on antipsychotics for a prolonged period are more severely ill than those not on antipsychotics. However, there are no clear features on which everyone would agree distinguishing "more severely ill people with schizophrenia". Nor is it always clear what "severity" means in relation to schizophrenia. One frequently used criterion for severity refers to more blatant psychotic illness. However, some episodes of blatant psychosis clear up quickly and thus these psychotic patients may not be more severely ill in every respect. Another potential criterion for severity in people with schizophrenia involves those whose disorder is more likely to be sustained over a longer period of time, or who have a poorer long-term prognosis. To control for this possible confounder, we have utilized the prognostic indices outlined by Vaillant, Stephens and Zigler. These were collected in our studies at index hospitalization. Later we compared the long-term outcome of poor-prognosis schizophrenia patients medicated with antipsychotics for 15-20 years to that of poor-prognosis patients not prescribed antipsychotics for 15-20 years. We also compared a good-prognosis sample of patients prescribed antipsychotics for 15-20 years with a good-prognosis sample of patients not prescribed antipsychotics for 15-20 years. In both comparisons, those patients not on antipsychotics for 15-20 years had fewer symptoms and better outcomes after the first 2-3 years3. An additional limitation of Correll et al's paper is that they do not fully address the evidence on dopamine supersensitivity psychosis from animals and from humans. They limit their discussion to short-term studies of psychotic relapse and the potential loss of antipsychotic efficacy, while ignoring the serious risk for the syndrome resulting from continuous long-term antipsychotic treatment. The clinical picture of dopamine supersensitivity psychosis is well defined and occurs with increasing frequency after two to three years of continuous antipsychotic maintenance use. Studies indicate that the syndrome manifests in 70% of patients with treatment resistant schizophrenia11. Other studies show that the switch to aripiprazole, mentioned by the authors, may actually unmask and intensify psychotic symptoms previously suppressed by stronger D2 antagonists12. While long-term continuous use of antipsychotics may induce the syndrome, these medications also block psychotic symptoms, which therefore remain largely unrecognized until the "breakthrough" of more severe symptoms occurs and leads to treatment resistance. While several research groups have described dopamine supersensitivity psychosis as a serious risk of long-term continuous use of antipsychotics, there has been a systematic failure to incorporate this finding into the risk-benefit ratio for continuous use of antipsychotics. The same applies to the possible negative impact of long-term antipsychotic treatment on work functioning3: the block of dopamine receptors may indeed reduce drive and motivation. Unfortunately, views about the long-term efficacy of antipsychotics are often based on the results from short-term (0-2 years) evaluations. As we have highlighted, there are at least eight major studies which fail to find better outcomes for schizophrenia patients treated on a long-term basis with antipsychotics. These negative results from multiple large well-documented long-term studies are a clear warning sign. Martin Harrow, Thomas H. Jobe Department of Psychiatry, University of Illinois at Chicago, College of Medicine, Chicago, IL, USA

To assess the long-term effectiveness of antipsychotic medications in facilitating work functioning in patients with schizophrenia we conducted longitudinal multifollowup research on 139 initially psychotic patients. The 70 patients with schizophrenia and 69 initially psychotic mood disordered control patients were followed up 6 times over 20 years. We compared the influence on work functioning of patients with schizophrenia continuously prescribed antipsychotics with patients with schizophrenia not prescribed antipsychotics, using statistical controls for inter-subject differences. While antipsychotics reduce or eliminate flagrant psychosis for most patients with schizophrenia at acute hospitalizations, four years later and continually until the 20 year followups, patients with schizophrenia not prescribed antipsychotics had significantly better work functioning. The work performance of the patients who were continuously prescribed antipsychotics was at a low rate and did not improve over time. Multiple other factors also interfere with work functioning. The data suggest that some patients with schizophrenia not prescribed antipsychotics for prolonged periods can function relatively well. Multiple other factors are associated with poor post-hospital work performance. The longitudinal data raise questions about prolonged treatment of schizophrenia with antipsychotic medications.

Background This research assesses whether multi-year treatment with antipsychotic medications reduces or eliminates psychosis in schizophrenia. It provides 20 years of longitudinal data on the frequency and severity of psychotic activity in samples of schizophrenia patients (SZ) treated versus those not treated with antipsychotic medications. Method A total of 139 early young schizophrenia and mood-disordered patients were assessed at index hospitalization and then reassessed six times over 20 years for psychosis and other major variables. Results At each follow-up assessment over the 20 years, a surprisingly high percentage of SZ treated with antipsychotics longitudinally had psychotic activity. More than 70% of SZ continuously prescribed antipsychotics experienced psychotic activity at four or more of six follow-up assessments over 20 years. Longitudinally, SZ not prescribed antipsychotics showed significantly less psychotic activity than those prescribed antipsychotics (p < 0.05). Conclusions The 20-year data indicate that, longitudinally, after the first few years, antipsychotic medications do not eliminate or reduce the frequency of psychosis in schizophrenia, or reduce the severity of post-acute psychosis, although it is difficult to reach unambiguous conclusions about the efficacy of treatment in purely naturalistic or observational research. Longitudinally, on the basis of their psychotic activity and the disruption of functioning, the condition of the majority of SZ prescribed antipsychotics for multiple years would raise questions as to how many of them are truly in remission.

Earlier randomised controlled trials (RCTs) for first-generation antipsychotics (FGA) comparing long-acting injectable antipsychotics (LAIs) to oral antipsychotics (OAPs) suggested FGA-LAIs were superior at preventing relapse. By delivering a full-recommended dose on a continuous basis, LAIs would seem to overcome adherence issues associated with OAPs.1

Antipsychotic medications are viewed as cornerstones for both the short-term and long-term treatment of schizophrenia. However, evidence on long-term (10 or more years) efficacy of antipsychotics is mixed. Double-blind discontinuation studies indicate significantly more relapses in unmedicated schizophrenia patients in the first 6-10 months, but also present some potentially paradoxical features. These issues are discussed.

It was in 1997 that we first discovered fuzzy logic and met Lotfi Zadeh. Our interest in the implication of fuzzy logic for medicine led us to pursue an academic interest in Zadeh’s contribution to science in its general implication. The most obvious point of relevance was that all of the so called “evidence based” clinical practice in medicine and experimentation level were intricately rooted in Aristotelian logic, probabilities and had in a significant organized fashion removed itself from fundamental discovery. Moreover, why had physician scientists accepted a method which allowed for the possibility of “chance” when someone’s life or all the future of therapeutic ventures were at stake? The underlying philosophy to contend with was that which said that no physician or scientist could ever completely master the truth of how or why the clinical state was as it presented before or after therapeutic intervention. This knowledge had to be founded in a gamble. All this was far removed from mastering the principles of physiology, chemistry and biologic systems.

Causation is one subject of science. It is also that of medicine because the physician aims to cause change in the clinical course of the ill patient. Scientific clinical medicine has adopted the view that cause is determined by observations then subjected to analysis. The method adopted for the analysis is probability theory. Probability measures generate numerically precise predictions. But, whereas this method commits prediction to the group level, the physician must treat the individual patient. In this paper we take a different approach to how the physician, prior to the application of group level evidence, and without accepting chance, thinks about causation. The causal analysis concerns the process itself of clinical course in the patient. We use the unit hypercube and fuzzy subsethood to formally capture the principles of both the physician's thought process and the dynamic of the clinical course of the patient.

BackgroundThe prevailing standard of care in the field involves background assumptions about the importance of prolonged use of antipsychotic medications for all schizophrenia (SZ) patients. However, do all SZ patients need antipsychotics indefinitely? Are there factors that help to identify which SZ patients can enter into prolonged periods of recovery without antipsychotics? This 20-year longitudinal research studied these issues.MethodA total of 139 early young psychotic patients from the Chicago Follow-up Study, including 70 patients with SZ syndromes and 69 with mood disorders, were assessed, prospectively, at the acute phase and then followed up six times over the next 20 years. Patients were assessed with standardized instruments for major symptoms, psychosocial functioning, personality, attitudinal variables, neurocognition and treatment.ResultsAt each follow-up, 30–40% of SZ patients were no longer on antipsychotics. Starting at the 4.5-year follow-ups and continuing thereafter, SZ patients not on antipsychotics for prolonged periods were significantly less likely to be psychotic and experienced more periods of recovery; they also had more favorable risk and protective factors. SZ patients off antipsychotics for prolonged periods did not relapse more frequently.ConclusionsThe data indicate that not all SZ patients need treatment with antipsychotics continuously throughout their lives. SZ patients not on antipsychotics for prolonged periods are a self-selected group with better internal resources associated with greater resiliency. They have better prognostic factors, better pre-morbid developmental achievements, less vulnerability to anxiety, better neurocognitive skills, less vulnerability to psychosis and experience more periods of recovery.

Objectives. To develop and evaluate a feedback method for reducing empathic errors in psychotherapy. Design. Randomized controlled trial conducted in a university-affiliated out-patient psychiatric clinic. Methods. Sixteen non-psychotic patients treated for Axis I disorders by 12 psychiatry residents were randomly assigned to intervention and control conditions. In both conditions, at the end of each session, patients rated their own functioning on the Global Assessment of Functioning scale, and therapists predicted patients' ratings. Patients predicted their therapist's accuracy and therapists rated their confidence in their own predictions. In the intervention condition, therapists and patients reviewed their respective ratings from the previous session together. In the control condition, ratings were given directly to the investigator without being reviewed by either patients or therapists. Results. Therapists in the intervention condition showed greater overall accuracy than controls as well as evidence of increasing empathy later in therapy on the Barrett-Lennard empathy subscale. Patients in the control group perceived their therapists as significantly more or less accurate than was warranted according to the accuracy measure (over-/under-idealization). Therapists in the control group were more likely than those in the intervention group to overestimate their own accuracy (overconfidence). Affective responses to the instrument were positive overall and did not differ by condition. Conclusion. An intervention such as the one tested in this study may be a practical and useful method for improving accuracy of understanding in a variety of training and clinical settings.

OBJECTIVESTo develop and evaluate a feedback method for reducing empathic errors in psychotherapy.DESIGNRandomized controlled trial conducted in a university-affiliated out-patient psychiatric clinic.METHODSSixteen non-psychotic patients treated for Axis I disorders by 12 psychiatry residents were randomly assigned to intervention and control conditions. In both conditions, at the end of each session, patients rated their own functioning on the Global Assessment of Functioning scale, and therapists predicted patients' ratings. Patients predicted their therapist's accuracy and therapists rated their confidence in their own predictions. In the intervention condition, therapists and patients reviewed their respective ratings from the previous session together. In the control condition, ratings were given directly to the investigator without being reviewed by either patients or therapists.RESULTSTherapists in the intervention condition showed greater overall accuracy than controls as well as evidence of increasing empathy later in therapy on the Barrett-Lennard empathy subscale. Patients in the control group perceived their therapists as significantly more or less accurate than was warranted according to the accuracy measure (over-/under-idealization). Therapists in the control group were more likely than those in the intervention group to overestimate their own accuracy (overconfidence). Affective responses to the instrument were positive overall and did not differ by condition.CONCLUSIONAn intervention such as the one tested in this study may be a practical and useful method for improving accuracy of understanding in a variety of training and clinical settings.