Valeria Savoja

Neurodevelopment in Schizophrenia: The Role of the Wnt Pathways

Objectives. To review the role of Wnt pathways in the neurodevelopment of schizophrenia. Methods: Systematic PubMed search, using as keywords all the terms related to the Wnt pathways and crossing them with each of the following areas: normal neurodevelopment and physiology, neurodevelopmental theory of schizophrenia, schizophrenia, and antipsychotic drug action. Results: Neurodevelopmental, behavioural, genetic, and psychopharmacological data point to the possible involvement of Wnt systems, especially the canonical pathway, in the pathophysiology of schizophrenia and in the mechanism of antipsychotic drug action. The molecules most consistently found to be associated with abnormalities or in antipsychotic drug action are Akt1, glycogen synthase kinase3beta, and beta-catenin. However, the extent to which they contribute to the pathophysiology of schizophrenia or to antipsychotic action remains to be established. Conclusions: The study of the involvement of Wnt pathway abnormalities in schizophrenia may help in understanding this multifaceted clinical entity; the development of Wnt-related pharmacological targets must await the collection of more data.

The wnt pathway in mood disorders

Objectives: To review the evidence of the involvement of the Wnt signalling pathway in mood disorders and in the action of drugs used to treat these disorders. Methods: We performed a careful PubMed search using as keywords all possible terms relevant to the Wnt pathway and crossing them with each of four areas, i.e., developmental effects, behavioural effects, mood disorders, and drugs used in their treatment. Papers were selected on the basis of their content and their data used for discussion. Results: Neurodevelopmental and behavioural data point to the possibility of involvement of the Wnt pathway in the pathophysiology of mood disorders. Clinical and post-mortem data are not sufficient to corroborate a definite role for Wnt alterations in any mood disorder. Combining genetic and pharmacological data, we may state that glycogen synthase kinase is the key molecule in bipolar disorder, as it is connected with many other signalling pathways that were shown to be involved in mood disorders, while Wnt molecules in the hippocampus appear to be mainly involved in depressive disorders. Conclusions: Altered Wnt signalling may play a role in the pathophysiology of mood disorders, although not a central one. It is premature to draw conclusions regarding the possible usefulness of Wnt manipulations in the treatment of mood disorders.

Neurocognition under hypnosis: Findings from recent functional neuroimaging studies

Abstract Functional neuroimaging studies show that hypnosis affects attention by modulating anterior cingulate cortex activation and uncoupling conflict monitoring and cognitive control function. Considering functional changes in the activation of the occipital and temporal cortices, precuneus, and other extrastriate visual areas, which account for hypnosis-induced altered reality perception, the role of mental imagery areas appears to be central under hypnosis. This is further stressed by the fact that motor commands are processed differently in the normal conscious state, deviating toward the precuneus and extrastriate visual areas. Functional neuroimaging also shows that posthypnotic suggestions alter cognitive processes. Further research should investigate the effects of hypnosis on other executive functions and personality measures.

Pain Perception and Hypnosis: Findings From Recent Functional Neuroimaging Studies

Abstract Hypnosis modulates pain perception and tolerance by affecting cortical and subcortical activity in brain regions involved in these processes. By reviewing functional neuroimaging studies focusing on pain perception under hypnosis, the authors aimed to identify brain activation-deactivation patterns occurring in hypnosis-modulated pain conditions. Different changes in brain functionality occurred throughout all components of the pain network and other brain areas. The anterior cingulate cortex appears to be central in modulating pain circuitry activity under hypnosis. Most studies also showed that the neural functions of the prefrontal, insular, and somatosensory cortices are consistently modified during hypnosis-modulated pain conditions. Functional neuroimaging studies support the clinical use of hypnosis in the management of pain conditions.

Relationships between psychopathological variables and insight in psychosis risk syndrome and first-episode and multiepisode schizophrenia

Abstract Insight may vary across psychosis risk syndrome (PRS), first-episode schizophrenia (FES), or multiepisode schizophrenia (MES). We aimed to compare insight domains (awareness, relabeling, and compliance) in PRS, FES, and MES groups and to correlate scores with psychopathological measures. Insight was assessed in 48 (14 PRS, 16 FES, and 18 MES) patients using the Schedule for the Assessment of Insight–Expanded Version. We conducted psychopathological assessment through the Brief Psychiatric Rating Scale (BPRS). In the whole group, the BPRS psychosis factor correlated with all insight domains. In the MES group, the more severe the anxiety/depression, the higher the insight score in the symptom relabeling domain. Insight did not differ significantly between the PRS, FES, and MES groups. Our results suggest that, across different phases of the illness, lack of insight behaves like a trait and is modulated by positive symptom severity. Anxiety and depression may be associated with increased insight in patients with chronic schizophrenia.

Effectiveness of Short-Term Olanzapine in Patients With Bipolar-I Disorder, With or Without Comorbidity With Substance Use Disorder

Objectives Prognosis of comorbid bipolar disorder (BD) and drug abuse is poor. We assessed the efficacy of olanzapine in manic or mixed BD patients, with (SUD) or without (N-SUD) comorbidity with substance use disorder (SUD) and its effect on drug abuse, days of abuse, and craving. Methods Eighty patients with BD-I (40 SUD) were hospitalized for a manic or mixed episode and received add-on olanzapine. Assessments were conducted at admission, discharge, and 4 and 8 weeks after discharge. Primary outcome was the proportion of responders and remitters in each group. We used a logistic regression model to adjust for possible confounders. We assessed craving and drug-abuse days with a visual analog scale and the Timeline Follow-Back. Results SUD and N-SUD were similar on response and remission, adjusted for sex, age, years ill, age at first episode, first episode depressive, number of hospitalizations, and duration of hospitalization (odds ratio, 1.09; 95% confidence interval, 1.02–2.29). Mood rating scores dropped significantly from baseline to end point in both groups. Timeline follow-back decreased in SUD from 22.5 to 7.3 at 8 weeks postdischarge, whereas craving dropped from 8.3 to 5.1 (P < 0.03). Conclusions The effectiveness of short-term olanzapine in BD-I mania or mixed mania did not differ according to SUD comorbidity. Treatment was followed by less substance use/abuse and craving in comorbid bipolar-SUD patients.

Hemochromatosis-induced bipolar disorder: A case report

OBJECTIVE A patient presenting with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, bipolar disorder was found to be affected by high iron hemochromatosis. This prompted us to explore the relation between bipolar disorder and iron overload. METHOD We report the case and review the peer-reviewed literature focusing on mood symptoms in patients with hemochromatosis or iron overload. Animal studies of brain effects of iron overload are summarized. High iron hemochromatosis was confirmed by genetic testing, and treatment was instituted to address iron overload. RESULTS Patients bipolar symptoms completely subsided after phlebotomic reduction of iron overload. CONCLUSION Clinicians should explore the possibility of iron overload and seek genetic confirmation of hemochromatosis in resistant bipolar disorder to avoid unnecessary medication.

Ethical questions in human clinical psychopharmacology: Should the focus be on placebo administration?

Of all ethical issues in clinical trial designs, only placebo use is dealt with acrimony and unwarranted, rhetoric emphasis. Many misconceptions are biased and may hamper research in the mechanisms of healing and recovery if placebo is banned from clinical trials, as some influential ethicists propose. Current treatments in psychiatry are by no means optimal and may vary in their effect across studies, rendering difficult to find the best available therapeutic method with which to compare new drugs. Because drugs possess specific mechanisms, it is not possible to compare drugs with different mechanisms as to their relevance in the pathophysiology of a given disorder. Placebo acts through non-specific mechanisms and is the ideal control for any disorder whose pathophysiology is relatively unknown and its treatment is still suboptimal. Sticking to short-term patient benefit in a trial reflects an individualistically oriented thinking in contemporary ethics and is likely to limit further research and efforts to better understand the mechanisms of disease and drug action, but also those related to general body reactance and self-healing, which are enhanced by placebo administration. Because in history ethics are swinging between two opposed views, it is possible that in the near future, the balance will move towards communitarianism, which is more likely to better serve long-term patient needs. Ethicists should also consider some other aspects of human experimentation, such as the consistency of research lines and the trend to substitute older drugs with their metabolites or enantiomers.

Improvement of cognition in a patient with Cotard's delusions and frontotemporal atrophy receiving electroconvulsive therapy (ECT) for depression

A 69-year-old man presented with Cotards delusions, insomnia, profound depression, amnesia, difficulty concentrating, and cognitive deficit after two different surgical interventions. Brain imaging showed frontotemporal-subcortical atrophy and lateral ventricular enlargement. He responded poorly to a combination of sertraline, amisulpride and mirtazapine, with modest benefit on insomnia, and developed hypotension. After 18 days he was switched to olanzapine and venlafaxine, but his cognition worsened. He underwent bilateral electroconvulsive therapy (ECT). His mood improved, cognitive performance increased and anxiety symptoms remitted. This improvement persisted through the one-month post-discharge follow-up and depression eventually remitted.

Short-Term Psychodynamic Psychotherapy in Patients with “Male Depression” Syndrome, Hopelessness, and Suicide Risk: A Pilot Study

Objectives and Methods. This was an observational study of the efficacy of short-term psychodynamic psychotherapy (STPP) in a sample of 35 (30 women and 5 men) patients with moderate-to-severe “male depression” (Gotland Scale for Male Depression (GSMD) ≥ 13) comorbid with unipolar mood disorder (dysthymia and major depression) or anxiety disorder. Outcome measures were GSMD and BHS (Beck Hopelessness Scale) score changes from baseline. Results. Patients had a strong response to STPP on the GSMD (estimated mean score change (± SE) = −9.08 ± 2.74; P < 0.01; partial eta squared = 0.50), but not on the BHS (estimated mean score change (± SE) = −0.92 ± 1.55; P = 0.57; partial eta squared   = 0.03). BHS score changes were significantly associated with GSMD score changes (Pearsons r = 0.56; P < 0.001), even when controlling for the severity of hopelessness at the baseline (partial r = 0.62; P < 0.001). Conclusions. STPP proved to be effective in patients suffering from “male depression” although hopelessness was only marginally reduced by this treatment which points to the need to better understand how STPP can be involved in the reduction of suicide risk.