Major depressive disorder (MDD) is a growing health problem. Current treatment options are not always effective and take several weeks of regular administration before an improvement can be seen in symptoms. Sub-anaesthetic doses of ketamine have been found to have antidepressant effects in previously treatment-resistant MDD after just one dose. However, ketamine also produces short term psychosis-like side effects which are undesirable for MDD patients. Ketamine is known to be an NMDA receptor antagonist, binding within the channel pore to block ion flow, however the molecular mechanism(s) underlying its antidepressant and psychosis-like effects are still unclear. In this thesis several genetically modified mouse lines were used to probe the molecular events involved in ketamine's actions. Firstly, a mouse line in which the c-terminal domain (CTD) of the NMDAR subtype GluN2B had been replaced with that of GluN2A, and a second line in which the opposite replacement had taken place, were used to investigate the role of the CTD in the NMDAR response to ketamine. It was found that the GluN2B CTD is required for the short-term psychosis-like response to a sub-anaesthetic dose of ketamine. This is interesting as the channel pore region, containing the binding site for ketamine, is unaltered in these mutants. Therefore, this finding implicates GluN2B CTD specific intracellular signalling molecules in this action of ketamine and raises the question of whether the CTD itself is able to respond to ketamine binding within the pore to induce signalling changes, perhaps via a conformational change. Secondly, a mouse line, in which the activity-regulated synaptic protein Arc has been tagged with a fluorescent marker, was used to investigate the response of synapses to both anaesthetic and sub-anaesthetic doses of ketamine. In this experiment tagged Arc protein was visible as punctate accumulations at synapses. A novel method termed 'synaptome mapping' was used to image these accumulations across entire coronal sections and to quantify their number, size and intensity. Using this method alterations to the Arc synaptome map were detected 1h, 6h and 24h following ketamine administration. The two doses used produced different changes to this map, with the sub-anaesthetic antidepressant dose inducing increases in Arc puncta number across many brain regions, whereas the anaesthetic dose induced short term (1h) increases followed by longer term decreases in Arc puncta number. This finding links long-term increases in Arc at the synapse with an antidepressant response to ketamine.

Background An increasing body of research is suggesting that childhood trauma and adversity may be associated with various adverse mental health outcomes, including psychosis. Cognitive functioning is often compromised in psychosis, and research has shown that there may be a link between early trauma and cognitive impairment in people with psychosis. No systematic review of the literature of this link has been undertaken, and very few studies have examined samples of individuals at high clinical risk for psychosis, to assess whether the potential link between adversity and cognitive functioning exists, without the confounding factors of length of illness, antipsychotic medication and chronicity of symptoms. Method The systematic review of all relevant electronic databases investigates the research to date on the association between childhood adverse experiences and cognitive ability in psychosis, and the conclusions that can be drawn from the existing literature, taking into account relevant considerations regarding sample, methodology and statistical analysis. The subsequent empirical study utilizes a sample at clinical high risk of developing psychosis, and a healthy control group to investigate whether any putative association in specific domains of cognitive functioning, or global cognitive ability and childhood adversity exist in those at clinical high risk, compared to controls. Results The systematic review indicated that at present, the literature looking into childhood adversity and cognitive ability in relation to psychosis is heterogeneous, with some studies finding that this association only occurs in patients, whilst others suggest it only occurs in the control groups. Some studies found it to be specific to certain cognitive domains, whilst others suggest it was a more global impairment. Methodology, samples and analysis differed considerably across studies, and likely contribute to the heterogeneity of the literature. The empirical paper showed a significant interaction effect between group (high risk versus controls) in the high childhood adversity group, in relation to global cognitive ability. Interestingly, this was not related to psychotic symptom severity or distress. Conclusion Several limitations of the existing studies limit the conclusions that can be drawn from the existing evidence regarding the link between childhood adversity and cognitive ability, and future research in prodromal samples is essential. The empirical study showed that there is a link between childhood adversity and cognitive ability in those at clinical high risk of developing psychosis, before disorder onset, that is not present in controls. This suggests that this may form a vulnerability in those at high risk for psychosis, rather than a more general mechanism present in the typical population.

Psychotic symptoms are prevalent in a wide variety of psychiatric and neurological disorders. Yet, despite decades of research, the neurobiological mechanisms via which these symptoms come to manifest themselves remain to be elucidated. I argue in this thesis that using a mechanistic approach towards understanding psychosis that borrows heavily from the predictive coding framework, can help us understand the relationship between neurobiology and symptomology. In the first results chapter I present new data on a biomarker that has often been cited in relation to psychotic disorders, which is glutamate levels in the anterior cingulate cortex (ACC), as measured with magnetic resonance spectroscopy. In this chapter I aimed to replicate previous results that show differences in glutamate levels in psychosis and health. However, no statistically significant group differences and correlations with symptomology were found. In order to elucidate the potential mechanism underlying glutamate changes in the anterior cingulate cortex in psychosis, I tested whether a pharmacological challenge of Bromocriptine or Sulpiride altered glutamate levels in the anterior cingulate cortex. However, no significant group differences were found, between medication groups. In the second results chapter I aimed to address a long-standing question in the field of computational psychiatry, which is whether prior expectations have a stronger or weaker influence on inference in psychosis. I go on to show that this depends on the origin of the prior expectation and disease stage. That is, cognitive priors are stronger in first episode psychosis but not in people at risk for psychosis, whereas perceptual priors seem to be weakened in individuals at risk for psychosis compared to healthy individuals and individuals with first episode psychosis. Furthermore, there is some evidence that these alterations are correlated with glutamate levels. In the third results chapter I aimed to elucidate the nature of reward prediction error aberrancies in chronic schizophrenia. There has been some evidence suggesting that schizophrenia is associated with aberrant coding of reward prediction errors during reinforcement learning. However it is unclear whether these aberrancies are related to disease years and medication use. Here I provide evidence for a small but significant alteration in the coding of reward prediction errors that is correlated with medication use. In the fourth results chapter I aimed to study the influence of uncertainty on the coding of unsigned prediction errors during learning. It has been hypothesized by predictive coding theorists that dopamine plays a role in the precision-weighting of unsigned prediction error. This theory is of particular relevance to psychosis research, as this might provide a mechanism via which dopamine aberrancies, might lead to psychotic symptoms. I found that blocking dopamine using Sulpiride abolishes precision-weighting of unsigned prediction error, providing evidence for a dopamine mediated precision-weighting mechanism. In the fifth results chapter I aimed to extend this research into early psychosis, to elucidate whether psychosis is indeed associated with a failure to precision-weight prediction error. I found that first episode psychosis is indeed associated with a failure to precision-weight prediction errors, an effect that is explained by the experience of positive symptoms. In the sixth results chapter I explore whether the degree of precision-weighting of unsigned prediction errors is correlated with glutamate levels in the anterior cingulate cortex. Such a correlation might be plausible given that psychosis has been associated with both. However, I did not find such a relationship, even in a sample of 137 individuals. Thus I concluded that anterior cingulate glutamate levels might be more related to non-positive symptoms associated with psychotic disorders. In summary, a mechanistic approach towards understanding psychosis can give us valuable insights into the disease mechanisms at play. I have shown here that the influence of expectations on perception is different across disease stage in psychosis. Furthermore, aberrancies in prediction error mechanisms might explain positive symptoms in psychosis, a process likely mediated by dopaminergic mechanisms, whereas evidence for glutamatergic mediation remains absent.

Given the heterogeneity of symptoms allowed in the diagnosis of psychotic disorders, as well as other challenges of categorical diagnosis (e.g., First et al., 2002; Krueger, 1999), the increased specificity brought by dimensional ratings of underlying features is often important. Models using the factorial structure of psychotic symptoms perform as good as or better than traditional categorical models (Allardyce, Suppes, & Van Os, 2007). DSM-5 has provided such a system of ratings to aid clinicians, the Clinician Rated Dimensions of Psychosis Symptom Severity Scale (PSS; APA, 2013). In this approach, the clinician rates symptom severity in eight domains which emphasize traditional psychotic symptomatology, cognition, and mood. Given its accessibility and the support of the DSM-5, it is possible that the measure could achieve wide use. However, little is known about the measure and the challenges of applying it in clinical settings. This study is a conceptual analysis of the conceptual foundation of the PSS, including its psychometric properties, applications, and demonstrated validity. It is also compared to the widely used Brief Psychiatric Rating Scale – Revised (BPRS-R). The PSS is more concise that other measures, and five of the PSS domains parallel the DSM-5's "Key Features That Define the Psychotic Disorders" (p. 87-88) (although the brief instructions of the PSS differ at times from DSM-5 definitions, and little in the way of definition is offered in the PSS itself). In contrast, no rationale is given for adding the remaining three domains. The dimensional model of the PSS has similarities to the factor structure typically found for symptomatology in psychotic disorder, but a number of important differences are noted. The data required for making ratings is never defined, although the only mention of data that might be helpful for rating one of the domains depends upon extensive testing. Although anchors for the ratings might, at first glance, appear to be given in the PSS, in fact, they offer almost nothing beyond the adjectives of "equivocal," "mild," "moderate," and "severe." Finally, we found that very little research exists on the PSS, no field trial was done, psychometric properties are largely unknown, and normative data is unavailable. The PSS is brief and provides a quick way to rate the severity of the five key features of psychosis required by DSM-5 diagnoses. Thus, it can work as a quick quantification of these features. Beyond this its utility is unknown, and it appears to lack the specificity of other rating scales, such as the BPRS-R.

<p>Motivation deficits remain an unmet treatment need in schizophrenia. Recent preclinical research has identified novel mechanisms underlying motivation deficits, namely impaired effort-cost computations and reduced future reward-value representation maintenance, that may serve as more effective treatment targets to improve motivation. The main aim of this study was to test the feasibility and preliminary effectiveness of a translational mechanism-based intervention, MEMS (Mobile Enhancement of Motivation in Schizophrenia), which leverages mobile technology to target these mechanisms with text-messages. Fifty-six participants with a schizophrenia-spectrum disorder were randomized to MEMS (<i>n</i> = 27) or a control condition (<i>n</i> = 29). All participants set recovery goals to complete over eight-weeks. The MEMS group also received personalized, interactive text-messages each weekday to support motivation. Retention and engagement in MEMS was high: 92.6% completed 8 weeks of MEMS, with an 86.1% text-message response rate, and 100% reported that they were satisfied with the text-messages. Compared to the control condition, the MEMS group had significantly greater improvements in interviewer-rated motivation and anticipatory pleasure and obtained significantly more recovery-oriented goals at the end of the 8-week period. There were no significant group differences in performance-based effort-cost computations and future reward-value representations, self-reported motivation, quality of life, functioning, or additional secondary outcomes of positive symptoms, mood symptoms, or neurocognition. Results suggest that MEMS is feasible as a relatively brief, low-intensity mobile intervention that could effectively improve interviewer-rated motivation, anticipatory pleasure, and recovery goal attainment in those with schizophrenia-spectrum disorders. </p>

Auditory Verbal Hallucinations (AVH) are a generally distressing phenomena that can have a negative impact on the quality of life of the experiencer. Furthermore, individuals diagnosed with psychotic disorders often display deficits in social/cognitive domains. Despite this, little is known about how AVHs directly affect social functioning and mental status. Because of this dearth of information, exploratory research is needed to generate potential avenues for future experimental research. Qualitative themes about how AVHs influence behavior were derived from interviews with mental health social workers. Eight primary domains were identified: Behavior, social ability, observable traits, voice plasticity, life difficulty, beneficial auditory hallucinations, coping strategies, and stigmas. Implications of this research could guide future direction for experimental research as well as contribute to assessment and treatment procedures of psychotic individuals.

No description available.

Bakgrund: En psykossjukdom är en sjukdom som inte bara drabbar personen själv utan hela dennes familj. Hela familjens livsvärld påverkas och familjelivet ansträngs hårt. Den psykossjuka familjemedlemmen erfar världen på ett annorlunda sätt. Vanliga symtom vid en psykos är bland annat hallucinationer och vanföreställningar. En bra vårdrelation mellan vårdgivare, den sjuka psykossjuka familjemedlemmen och anhöriga är en förutsättning för återhämtning. Syfte: Få ökad kunskap om och förståelse för anhörigas upplevelse av att leva med en familjemedlem med psykossjukdom. Metod: Metoden som valdes för studien var en systematisk litteraturstudie i vilken elva vetenskapliga artiklar analyserades med en kvalitativ innehållsanalys. Resultat: Tre kategorier framträdde ur data. Dessa visar att anhöriga bär på både känslomässiga och praktiska bördor samt att de har negativa erfarenheter av stöd och information av vårdpersonal. Slutsats: Resultatet i studien visar att psykossjukdom är en belastande sjukdom för anhöriga. Deras känslomässiga bördor är komplexa beroende på deras höga belastning av att vårda sin sjuka familjemedlem samt brister i bemötande av vårdpersonal.

Syfte: Syftet med litteraturstudien var att beskriva hur sjuksköterskor upplevde omvårdanden av patienter med psykos inom psykiatrisk öppen- samt slutenvård. Bakgrund: Allmänheten har än idag en negativ och felaktig bild av psykisk sjukdom samt psykiatrisk vård. Att vårda personer med psykos skiljer sig från arbetet med somatiska sjukdomar. Metod: En litteraturstudie genomfördes vilken baserades vetenskapliga artiklar som sökts i databaserna Cinahl och PsykInfo. Resultat: Omvårdnaden av patienter med psykos upplevdes som oförutsägbart vilket krävde ständig beredskap och mycket tålamod. Sjuksköterskorna upplevde att arbetet medförde stort ansvar. Att respektera patienternas självbestämmande, privatliv samt integritet var viktigt. Även att skapa en meningsfull och bestående relation ansågs som viktigt. I vissa fall kände sjuksköterskorna osäkerhet över hur de skulle bemöta patienterna. Det som sjuksköterskorna strävade efter var att få patienten att må så bra som möjligt. Diskussion: Två fynd valdes att diskuteras. Dessa var personlig involvering från sjuksköterskornas sida och en god relation var en förutsättning för att ge god omvårdnad. Att sjuksköterskorna upplevde blandade känslor i arbetet med patienterna är sunt och visade att sjuksköterskorna var engagerade i patienterna. Slutsats: I omvårdnaden av patienter med psykos skapas långa, nära relationer. Detta kan upplevas som påfrestande för sjuksköterskorna. Att samtala och diskutera med kollegor underlättar. Mer forskning inom ämnet bör göras för att försöka minimera fördomarna samt för att förbättra omvårdnaden av dessa patienter. / Aim: The aim of the literature review was to describe nurses experience of nursing patients suffering from psychosis in out- and inpatient settings. Background: In general people have a negative and wrong perception of psychiatric illness and psychiatric care. Psychiatric nursing is different from somatic nursing.  The difference is that in the case of psychosis you nurse the psyche and with the somatic diseases it is mainly physical ailments. Method: A literature review was conducted which was based on scientifically articles. These articles were found in the databases Cinahl and PsykInfo. Result: Caring for patients with psychosis was experienced as unpredictable which demanded constant readiness and a lot of patience. The nurses felt they had a big responsibility in there work. To respect the patients autonomy, private life and integrity was important. To create a lasting relationship was also considered important. In some cases the nurses felt insecurity about how they should encounter the patients. The nurses where striving to make the patients feel as good as possible. Discussion: Two findings were discussed: The nurses´ personal involvement and a god relationship is a condition to provide good nursing. The nurse’s felt mixed emotions in the work with the patients and this is a healthy behaviour that showed their engagement in the patients. Conclusion: Caring of patients with psychosis leads to long and close relationships. This may be perceived as stressful for the nurses. To talk and discuss with colleagues could help. More research within the area is needed to minimize prejudices and to improve the nursing of these patients.

Objective: To date there have been few if any qualitative studies of adults who have experienced childhood sexual abuse (CSA) followed by psychotic experiences later in life. This study aimed to explore how a sample of four women make sense of their childhood experiences of sexual abuse and their psychotic experiences later in life. Methodology: Data was gathered through semi-structured interviews with four women. The data were analysed using Interpretative Phenomenological Analysis (IPA) in order to develop a detailed understanding of the women’s search for meaning in their own lives. Results: Four major themes emerged from the analysis of the women’s accounts: ‘Interpersonal difficulties,’ ‘Striving to Get Better’ and ‘A Relationship with Shame’ and ‘Links Between CSA, Mental health & Psychosis’. These are explored in detail. Conclusions: The women’s accounts highlight the ongoing difficulty of living with psychosis and CSA, in particular, the role of psychosis in exacerbating isolation, shame and negative self perceptions. Attention is also drawn to the development of competence for therapists in this area of work. Clinical Implications: Supporting and validating existing healthy coping strategies as well as exploration of the interaction of psychosis and CSA through psychological mechanisms of shame as well as family / society discourses. Therapist/ researcher selfawareness is crucial in supporting clients with such traumatic histories.