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Cognitive-Behavioral Therapy (CBT) has a significant adjunctive effect in the treatment of Major Depressive Disorder (MDD), however its use as monotherapy in group-based approaches is less explored. We assessed the responses of distinct psychophysiological domains after a group-based CBT (gCBT, 16 weeks) intervention in drug-free patients with mild-moderate MDD (n = 20; women = 11) and compared them with a healthy control group (n = 25, women = 13). The treatment resulted in 65% of response and 55% of remission rates. Significant reductions in depressive and anxiety symptoms and increase in self-esteem and sleep quality were observed as gCBT responses. Moreover, after treatment, patients regulated their previously deregulated salivary cortisol awakening response and sleep quality toward healthy parameters. These improvements were correlated among themselves and dependent of remission outcome. Remitted patients showed larger improvements than non-remitted for all psychophysiological domains, except for serum cortisol that significantly changed only for no-remitted patients after gCBT but did not reached controls levels. Further, better baseline sleep quality was predictor of remission. The psychophysiological changes found support the use of gCBT as monotherapy treatment for mild-moderate MDD, corroborate the importance of the observation of the patients in theirs whole sociopsychophysiological condition since they are related to remission outcome and then stimulate further studies of validation of clinical protocols that work on all of these psychophysiological domains studied. Trial Registration U1111–1215-4472. Registered 21 August 2018, http://www.ensaiosclinicos.gov.br/rg/RBR-3npbf8/

The comprehension of the pathophysiology of the major depressive disorder (MDD) is essential to the strengthening of precision psychiatry. In order to determine the relationship between the pathophysiology of the MDD and its clinical progression, analyzed by severity of the depressive symptoms and sleep quality, we conducted a study assessing different peripheral molecular biomarkers, including the levels of plasma C-reactive protein (CRP), serum mature brain-derived neurotrophic factor (mBDNF), serum cortisol (SC), and salivary cortisol awakening response (CAR), of patients with MDD (n = 58) and a control group of healthy volunteers (n = 62). Patients with the first episode of MDD (n = 30) had significantly higher levels of CAR and SC than controls (n = 32) and similar levels of mBDNF of controls. Patients with treatment-resistant depression (TRD, n = 28) presented significantly lower levels of SC and CAR, and higher levels of mBDNF and CRP than controls (n = 30). An increased severity of depressive symptoms and worse sleep quality were correlated with levels low of SC and CAR, and with high levels of mBDNF. These results point out a strong relationship between the stages clinical of MDD and changes in a range of relevant biological markers. This can assist in the development of precision psychiatry and future research on the biological tests for depression.

Background: Ayahuasca is a traditional Amazon brew and its potential antidepressant properties have recently been explored in scientific settings. We conducted a double-blind placebo-controlled trial of ayahuasca with treatment-resistant depression patients ( n = 28) and healthy controls ( n = 45). Aims: We are evaluating the blood inflammatory biomarkers: C-reactive protein and interleukin 6, as a potential consequence of ayahuasca intake and their correlation with serum cortisol and brain-derived neurotrophic factor levels. Blood samples were collected at pre-treatment and 48 hours after substance ingestion to assess the concentration of inflammatory biomarkers, together with administration of the Montgomery-Åsberg Depression Rating Scale. Results: At pre-treatment, patients showed higher C-reactive protein levels than healthy controls and a significant negative correlation between C-reactive protein and serum cortisol levels was revealed ( rho = –0.40, n = 14). C-reactive protein in those patients was not correlated with Montgomery-Åsberg Depression Rating Scale scores. We observed a significant reduction of C-reactive protein levels across time in both patients and controls treated with ayahuasca, but not with placebo. Patients treated with ayahuasca showed a significant correlation ( rho = + 0.57) between larger reductions of C-reactive protein and lower depressive symptoms at 48 hours after substance ingestion (Montgomery-Åsberg Depression Rating Scale). No significant result with respect to interleukin 6 and brain-derived neurotrophic factor was found. Furthermore, these biomarkers did not predict the antidepressant response or remission rates observed. Conclusions: These findings enhance the understanding of the biological mechanisms behind the observed antidepressant effects of ayahuasca and encourage further clinical trials in adults with depression.

Sleep disturbance is a symptom consistently found in major depression and is associated with a longer course of illness, reduced response to treatment, increased risk of relapse and recurrence. Chronic insomnia has been associated with changes in cortisol and serum brain-derived neurotrophic factor (BDNF) levels, which in turn are also changed in major depression. Here, we evaluated the relationship between sleep quality, salivary cortisol awakening response (CAR), and serum BDNF levels in patients with sleep disturbance and treatment-resistant major depression (n = 18), and in a control group of healthy subjects with good (n = 21) and poor (n = 18) sleep quality. We observed that the patients had the lowest CAR and sleep duration of all three groups and a higher latency to sleep than the healthy volunteers with a good sleep profile. Besides, low CAR was correlated with more severe depressive symptoms and worse sleep quality. There was no difference in serum BDNF levels between groups with distinct sleep quality. Taken together, our results showed a relationship between changes in CAR and in sleep quality in patients with treatment-resistant depression, which were correlated with the severity of disease, suggesting that cortisol could be a physiological link between sleep disturbance and major depression.

Background: Recent evidence has shown improvements in schizophrenia symptoms after the infusion of sodium nitroprusside (SNP), a nitric oxide (NO) donor. In the rat model of schizophrenia using ketamine injection, pretreatment with SNP seems to prevent behavioral changes associated with positive symptoms for up to one week. Objective: We investigated whether SNP would have preventative effects on psychogenic symptoms induced by ketamine in healthy subjects. Methods: Healthy subjects (N = 38) were assigned to distinct groups that received SNP in different doses (0.15, 0.25, and 0.5 mcg/kg/min). First, participants received an infusion of SNP or placebo over 75 minutes. After 10 minutes, they were injected for 1 minute with a bolus of 0.26 mg/kg of ketamine and a maintenance dose was started 5 minutes later, with 0.25 mg/kg/h of ketamine for 50 minutes. Results: Ketamine-induced psychopathological alterations induced were reduced by SNP, as assessed with the Brief Psychological Rating Scale. Scores in the objective subscale of the Clinician-Administered Dissociative States Scale were also lower in SNP sessions compared to placebo. SNP had protective effects against deterioration in facial emotion and identity recognition tasks induced by ketamine. Discussion: Our findings support the view that SNP has preventative properties against psychotic manifestations.

BackgroundRecent open-label trials show that psychedelics, such as ayahuasca, hold promise as fast-onset antidepressants in treatment-resistant depression.MethodsTo test the antidepressant effects of ayahuasca, we conducted a parallel-arm, double-blind randomized placebo-controlled trial in 29 patients with treatment-resistant depression. Patients received a single dose of either ayahuasca or placebo. We assessed changes in depression severity with the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Hamilton Depression Rating scale at baseline, and at 1 (D1), 2 (D2), and 7 (D7) days after dosing.ResultsWe observed significant antidepressant effects of ayahuasca when compared with placebo at all-time points. MADRS scores were significantly lower in the ayahuasca group compared with placebo at D1 and D2 (p= 0.04), and at D7 (p< 0.0001). Between-group effect sizes increased from D1 to D7 (D1: Cohen'sd= 0.84; D2: Cohen'sd= 0.84; D7: Cohen'sd= 1.49). Response rates were high for both groups at D1 and D2, and significantly higher in the ayahuasca group at D7 (64%v.27%;p= 0.04). Remission rate showed a trend toward significance at D7 (36%v.7%,p= 0.054).ConclusionsTo our knowledge, this is the first controlled trial to test a psychedelic substance in treatment-resistant depression. Overall, this study brings new evidence supporting the safety and therapeutic value of ayahuasca, dosed within an appropriate setting, to help treat depression. This study is registered athttp://clinicaltrials.gov(NCT02914769).

Objective: The incidence rate of major depression in adolescents reaches approximately 14%. This disorder is usually recurrent, without remission of symptoms even after pharmacological treatment, and persists throughout adult life. Since the effects of antidepressants take approximately 2 weeks to begin, new pharmacological therapies are under continuous exploration. Recent evidence suggests that psychedelics could produce rapid antidepressant effects. In this study, we evaluated the potential antidepressant effects of ayahuasca in a juvenile non-human primate model of depression. Methods: While living with their families, juvenile marmosets (8 males; 7 females) were observed on alternate days for four weeks during a baseline phase. This was followed by 8 weeks of an induced depressive state protocol, the social isolated context (IC), in which the animals were monitored in the first and last weeks. Subsequently, five males and four females were randomly selected for treatment, first with a single administration of saline vehicle (1.67 mL/300 g of body weight, via gavage), followed by a single dose of ayahuasca (1.67 mL/300 g of body weight, via gavage). Both phases lasted 1 week and the animals were monitored daily. A third week of sampling was called the tardive-pharmacological effects phase. In all phases the marmosets were assessed for behavior, fecal cortisol levels, and body weight. Results: After IC, the animals presented typical hypocortisolemia, but cortisol recovered to baseline levels 24 h after an acute dose of ayahuasca; this recovery was not observed in vehicle-treated animals. Additionally, in males, ayahuasca, but not the vehicle, reduced scratching, a stereotypic behavior, and increased feeding. Ayahuasca treatment also improved body weight to baseline levels in both sexes. The ayahuasca-induced behavioral response had long-term effects (14 days). Thus, in this translational juvenile animal model of depression, ayahuasca presented beneficial effects. Conclusions: These results can contribute to the validation of ayahuasca as an antidepressant drug and encourage new studies on psychedelic drugs as a tool for treating mood disorders, including for adolescents with early-onset depression.

Major depression is a highly prevalent mood disorder, affecting about 350 million people, and around 30% of the patients are resistant to currently available antidepressant medications. Recent evidence from a randomized placebo-controlled trial supports the rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression. The aim of this study was to explore the effect of ayahuasca on plasma cortisol and awakening salivary cortisol response, in the same group of treatment-resistant patients and in healthy volunteers. Subjects received a single dose of ayahuasca or placebo, and both plasma and awakening salivary cortisol response were measured at baseline (before dosing) and 48h after the dosing session. Baseline assessment (D0) showed blunted awakening salivary cortisol response and hypocortisolemia in patients (DM), both with respect to healthy controls group (C). Salivary cortisol also was measured during dosing session and we observed a large increased for both C and DM that ingested ayahuasca, than placebo groups. After 48h of the dosing session (D2) with ayahuasca, awakening salivary cortisol response (for both sexes) of treated patients became similar to levels detected in controls. This was not observed in patients that ingested placebo. No changes in plasma cortisol were observed after 48 hours of ayahuasca or placebo ingestion for both groups and sexes. Therefore, these findings point to new evidence of modulation of ayahuasca on salivary cortisol levels, as cortisol acts in regulation of distinct physiological pathways, emotional and cognitive processes related to etiology of depression, this modulation could be an important part of the antidepressant effects observed with ayahuasca. Moreover, this study highlights the importance of psychedelics in the treatment of human mental disorders.

Objectives: Ayahuasca (AYA), a natural psychedelic brew prepared from Amazonian plants and rich in dimethyltryptamine (DMT) and harmine, causes effects of subjective well-being and may therefore have antidepressant actions. This study sought to evaluate the effects of a single dose of AYA in six volunteers with a current depressive episode. Methods: Open-label trial conducted in an inpatient psychiatric unit. Results: Statistically significant reductions of up to 82% in depressive scores were observed between baseline and 1, 7, and 21 days after AYA administration, as measured on the Hamilton Rating Scale for Depression (HAM-D), the Montgomery-A u sberg Depression Rating Scale (MADRS), and the Anxious-Depression subscale of the Brief Psychiatric Rating Scale (BPRS). AYA administration resulted in nonsignificant changes in Young Mania Rating Scale (YMRS) scores and in the thinking disorder subscale of the BPRS, suggesting that AYA does not induce episodes of mania and/or hypomania in patients with mood disorders and that modifications in thought content, which could indicate psychedelic effects, are not essential for mood improvement. Conclusions: These results suggest that AYA has fast-acting anxiolytic and antidepressant effects in patients with a depressive disorder.

Recently, we found a rapid and long-lasting improvement of symptoms in schizophrenic patients on antipsychotics after a single four-hour infusion of sodium nitroprusside (SNP), a nitric oxide (NO) donor with a short half-life. This improvement persisted for up to 4 weeks. Because these patients remained on antipsychotics after infusion of SNP was finished, the question arises about whether this improvement was due to SNP itself. We have now investigated whether SNP, alone, can produce preventive antipsychotic effects in rats treated with ketamine (KET). 56 adult rats divided into 7 groups were infused with SNP 4 mg/kg, KET 25 mg/kg, or saline as follows: group1 — saline, group2 — SNP, group3 — KET, group4 — KET 12 h after SNP, group5 — KET 1 day after SNP, group6 — KET 2 days after SNP, and group7 — KET 1 week after SNP. The animals were filmed in an open field arena for 30 min and the videos were later analyzed by ANY-Maze software to measure activity and stereotypy. SNP significantly prevented the emergence of hyperactivity induced by KET when it was administered for up to 1 week before KET, and prevented the emergence of stereotypies when it was administered for up to 1 day before KET. These findings in rats, which have an even faster metabolic rate than humans, suggest that the long-lasting effects observed in our clinical trial with SNP in humans could have been due to SNP itself, and indicate for the first time that SNP may present preventive antipsychotic effects.

Recent open label trials show that psychedelics, such as ayahuasca, hold promise as fast-onset antidepressants in treatment-resistant depression. In order to further test the antidepressant effects of ayahuasca, we conducted a parallel-arm, double-blind randomized placebo-controlled trial in 29 patients with treatment-resistant depression. Patients received a single dose of either ayahuasca or placebo. Changes in depression severity were assessed with the Montgomery–Åsberg Depression Rating Scale (MADRS) and the Hamilton Depression Rating scale (HAM-D). Assessments were made at baseline, and at one (D1), two (D2) and seven (D7) days after dosing. We observed significant antidepressant effects of ayahuasca when compared to placebo at all timepoints. MADRS scores were significantly lower in the ayahuasca group compared to placebo (at D1 and D2: p=0.04; and at D7: p

For many years the focus of neurochemical and pharmacological studies on schizophrenia was on dopamine, and that work yielded a great deal of information about the possible etiology of this debilitating disorder and contributed significantly to the development of antipsychotic drugs. However, it has become increasingly apparent that other neurotransmitters and neuromodulators must also play an important role, and in recent years there has been considerable interest in these other compounds and the systems related to them in the search for developing drugs that are more effective and have fewer side effects than the antipsychotics currently available. This review deals with three of those neurochemicals, namely glycine, D-serine and nitric oxide, and shows how an increased knowledge of them may be important in the future diagnosis and/or pharmacotherapy of schizophrenia.

Background: Recent findings suggest that dopaminergic abnormalities found in psychotic disorders may be secondary to nitric oxide dysfunctions. Nitric oxide seems to influence glutamatergic and dopaminergic neurotransmission, both of which have been associated with psychosis. Objective: To search and review published works which examined the influence of nitric oxide in psychotic disorders subjects. Method: The research was executed in the on-line collections of Pubmed and ISI Web of Science. The key aspects utilized were “Psychotic Disorders AND Nitric Oxide”, “Psychosis AND Nitric Oxide”,“Schizotypal Personality Disorder AND Nitric Oxide”, “Delusional Disorder AND Nitric Oxide”, “Brief Psychotic Disorder AND Nitric Oxide”, “Schizophreniform Disorder AND Nitric Oxide”, “Schizoaffective Disorder AND Nitric Oxide”, and “Schizophrenia AND Nitric Oxide”. Empirical works utilizing human subjects, published in the last 10 years, in English language were included. Results: Initially, the search yielded a total of 95 studies. Then, 39 were elected according to the inclusion requirements. The selected articles were divided into five groups: biochemical studies (n=15; 38.5%), genetic studies (n=11; 28.2%), postmortem studies (n=6; 15.4%), clinical trials (n=6; 15.4%), and case reports (n=1; 2.5%). The studies evaluated only schizophrenic or schizoaffective disorder subjects. The great majority of them found evidence of nitric oxide dysfunctions in psychosis. Conclusion: The results of the review strengthen the idea that nitric oxide has a key participation in psychotic disorders and deserves deeper investigation as a target for future pharmacological intervention.

This case report describes a patient with manic and psychotic symptoms who had a history of neurocysticercosis and presented with an episode of hypertensive hydrocephalus in 2003. Despite her history, she was initially treated for primary psychiatric disease.

Rationale The devastating nature of schizophrenia and treatment limitations have triggered a search for early detection methods to enable interventions to be implemented as soon as the first signs and symptoms appear. In this effort, several studies have investigated the cognitive functions in individuals regarded as being in at-risk mental states (ARMS) for psychosis. Objective Our aim was to make a systematic review of the literature regarding basic and social cognition in individuals in ARMS following the guidelines of the PRISMA statement. Results In general, the results of the 49 articles included in the review show that individuals in ARMS have pervasive cognitive deficits that seem to be greater in individuals who later convert to psychosis. Conclusions Cognitive impairment can be detected in individuals considered to be in ARMS according to current classifications and may serve as a risk marker for psychotic conversion; however, the lack of standardized criteria to define ARMS and of homogeneous cognitive assessment methods hamper the generalization of findings from different studies.

Background Better treatments for schizophrenia are urgently needed. The therapeutic use of the nitric oxide (NO)-donor sodium nitroprusside (SNP) in patients with schizophrenia has shown promising results. The role of NO in schizophrenia is still unclear, and NO modulation is unexplored in ketamine (KET) animal models to date. In the present study, we compared the behavioral effects of pre- and post-treatment with SNP, glyceryl trinitrate (GTN), and methylene blue (MB) in the acute KET animal model of schizophrenia. The present study was designed to test whether acute SNP, GTN, and MB treatment taken after (therapeutic effect) or before (preventive effect) a single KET injection would influence the behavior of rats in the sucrose preference test, object recognition task and open field. Results The results showed that KET induced cognitive deficits and hyperlocomotion. Long- term memory improvement was seen with the therapeutic GTN and SNP treatment, but not with the preventive one. MB pretreatment resulted in long-term memory recovery. GTN pre-, but not post-treatment, tended to increase vertical and horizontal activity in the KET model. Therapeutic and preventive SNP treatment consistently decreased KET-induced hyperlocomotion. Conclusion NO donors – especially SNP – are promising new pharmacological candidates in the treatment of schizophrenia. In addition, we showed that the potential impact of NO-related compounds on KET-induced behavioral changes may depend on the temporal window of drug administration.

“Schizophrenia is arguably the worst disease affecting mankind, even AIDS not excepted”. Since this statement in 1988 (Editors, 1988), schizophrenia still remains a major challenge to medicine, with up to 60% of patients not responding adequately to treatment despite the relatively large arsenal of antipsychotics currently available. By modulating the nitric oxide (NO) pathway, a new paradigm for schizophrenia treatment apparently involving modulation of nitric oxide (NO) has been proposed (Oliveira et al., 2011).

One of the subjects that most concerns physicians is treatment-resistance. About 30%–60% of schizophrenia patients do not respond adequately to antipsychotic treatment and are known as refractory schizophrenia patients. Clozapine has been the drug of choice in such cases. However, approximately 30% of them do not respond to clozapine either. Here, we describe a patient with an initial diagnosis of refractory schizophrenia who had a history of dramatic aggressiveness. However, in this case, “refractoriness” was a wrong diagnosis. A case of psychosis secondary to epilepsy had been treated as schizophrenia for almost 20 years. Reports like this one are important because they remind us of how a thorough investigation can lead to the correct diagnosis and improve the patient's prognosis.

Importance The treatment of schizophrenia remains a challenge, and the currently available antipsychotic drugs are slow acting and produce a number of adverse effects. Objective To examine the effectiveness and safety of a single intravenous administration of sodium nitroprusside (0.5 μg/kg/min for 4 hours) on the positive, negative, anxiety, and depressive symptoms in patients with schizophrenia. Design Single-center, randomized, double-blind, placebo-controlled trial performed from March 9, 2007, to March 12, 2009. Setting University teaching hospital in Sao Paulo, Brazil. Participants Twenty inpatients aged 19 to 40 years with a diagnosis of schizophrenia who were in the first 5 years of the disease who are taking antipsychotics. Intervention Sodium nitroprusside administration. Main Outcome Measures The 18-item Brief Psychiatric Rating Scale and the negative subscale of the Positive and Negative Syndrome Scale. Results After the infusion of sodium nitroprusside, a rapid (within 4 hours) improvement of symptoms was observed. The placebo and experimental groups had significant differences in the 18-item Brief Psychiatric Rating Scale total score and subscale scores, which persisted for 4 weeks after infusion. Conclusions The results clearly show a therapeutic effect of sodium nitroprusside. If this drug is approved for routine clinical use in patients with schizophrenia, this discovery will be an important advance in the pharmacologic treatment of this devastating disorder. Trial Registration clinicaltrials.gov Identifier:NCT01548612

For the last 40 years, schizophrenia has been considered to be the result primarily of a dysfunction in brain dopaminergic pathways. In this review, it is described and discussed findings concerning nitric oxide-mediated neurotransmission in schizophrenia. Studies were searched in PubMed, SciELO, and LILACS using the terms schizophrenia and nitric oxide plasma levels or nitric oxide serum levels, with no time limit. The reference lists of selected articles were also hand-searched for additional articles. From 15 potential reports, 10 were eligible to be included in the review and meta-analysis. These studies included a total of 505 patients with schizophrenia and 339 healthy volunteers. No significant difference was found between patients and healthy controls regarding total nitrite plasma/serum levels (effect size g = 0.285, 95%CI = -0.205 to 0.774, p = 0.254). However, when studies with patients under antipsychotic treatment were examined separately, there was a significant difference between patients and healthy volunteers (effect size g = 0.663, 95%CI = 0.365 to 0.961, p < 0.001), showing that patients under treatment have higher levels of plasma/serum nitric oxide than controls. These results suggest that antipsychotics increase nitric oxide plasma/serum levels and that the nitrergic pathway would be a fertile target for the development of new treatments for patients with schizophrenia. Durante os últimos 40 anos, a esquizofrenia foi considerada, principalmente, como o resultado de disfunções dopaminérgicas no cérebro. Esta revisão descreve e discute algumas descobertas sobre a neurotransmissão mediada pelo óxido nítrico na esquizofrenia. A busca foi feita nas bases PubMed, SciELO e LILACS usando-se os termos schizophrenia e nitric oxide plasma levels ou nitric oxide serum levels, sem limites de tempo. As listas de referências dos artigos selecionados foram examinadas em busca de outras publicações pertinentes. Dentre 15 artigos passíveis de serem incluídos, 10 preenchiam os critérios estabelecidos para a revisão e metanálise. Esses estudos incluíram 505 pacientes com esquizofrenia e 339 voluntários saudáveis. Não foram encontradas diferenças significativas entre pacientes e voluntários saudáveis quanto aos níveis plasmáticos de nitrito total (effect size g = 0,285, IC 95% = -0,205 a 0,774, p = 0,254). No entanto, o exame separado dos estudos envolvendo pacientes em tratamento antipsicótico apresentou diferenças significativas entre pacientes e voluntários saudáveis (effect size g = 0,663, IC 95% = 0,365 to 0,961, p < 0,001), demonstrando que pacientes em tratamento possuem níveis plasmáticos mais altos de óxido nítrico. Esses resultados sugerem que os antipsicóticos podem aumentar os níveis plasmáticos de óxido nítrico e que a via nitrérgica (e sua estimulação) constituiria um alvo propício para o desenvolvimento de novos tratamentos para pacientes com esquizofrenia.

Schizophrenia is a devastating disorder that occurs in about 1% of the population worldwide. For over 30 years, it has been considered to be the result of dysfunctional brain dopaminergic pathways. However, dopaminergic antipsychotic drugs have proven effective for only some of the symptoms found in schizophrenia patients. Recent evidence suggests that dopaminergic abnormalities may be secondary to dysfunctions in multi-neurotransmitter systems modulating dopamine. One of the key neurotransmitters thought to be involved in schizophrenia is glutamate, and there is strong support for the involvement of a hypoactivity of N-methyl-D-aspartate (NMDA) glutamate receptors in the pathogenesis of schizophrenia. However, research with NMDA receptor agonists for the treatment of schizophrenia has produced inconsistent results, which may be due to the development of rapid tolerance to these compounds secondary to down-regulation of NMDA receptors. Perhaps the development of drugs that act on targets downstream NMDA receptors, such as nitric oxide (NO), could avoid the problem of the down-regulation of these receptors.