Glutamate-N-methyl-D-aspartate receptor modulation and minocycline for the treatment of patients with schizophrenia: an update: [review]

Growing consistent evidence indicates that hypofunction of N-methyl-D-aspartate (NMDA) transmission plays a pivotal role in the neuropathophysiology of schizophrenia. Hence, drugs which modulate NMDA neurotransmission are promising approaches to the treatment of schizophrenia. The aim of this article is to review clinical trials with novel compounds acting on the NMDA receptor (NMDA-R). This review also includes a discussion and translation of neuroscience into schizophrenia therapeutics. Although the precise mechanism of action of minocycline in the brain remains unclear, there is evidence that it blocks the neurotoxicity of NMDA antagonists and may exert a differential effect on NMDA signaling pathways. We, therefore, hypothesize that the effects of minocycline on the brain may be partially modulated by the NMDA-R or related mechanisms. Thus, we have included a review of minocycline neuroscience. The search was performed in the PubMed, Web of Science, SciELO, and Lilacs databases. The results of glycine and D-cycloserine trials were conflicting regarding effectiveness on the negative and cognitive symptoms of schizophrenia. D-serine and D-alanine showed a potential effect on negative symptoms and on cognitive deficits. Sarcosine data indicated a considerable improvement as adjunctive therapy. Finally, minocycline add-on treatment appears to be effective on a broad range of psychopathology in patients with schizophrenia. The differential modulation of NMDA-R neurosystems, in particular synaptic versus extrasynaptic NMDA-R activation and specific subtypes of NMDA-R, may be the key mediators of neurogenesis and neuroprotection. Thus, psychotropics modulating NMDA-R neurotransmission may represent future monotherapy or add-on treatment strategies in the treatment of schizophrenia.

Proton magnetic resonance spectroscopy of the frontal, cingulate and perirolandic cortices and its relationship to skin conductance in patients with schizophrenia

The aim of the present study was to determine whether specific subgroups of schizophrenic patients, grouped according to electrodermal characteristics, show differences in the N-acetylaspartate/creatine plus choline (NAA / (Cr + Cho)) ratios in the frontal, cingulate and perirolandic cortices. Skin conductance levels (SCL) and skin conductance responses to auditory stimulation were measured in 38 patients with schizophrenia and in the same number of matched healthy volunteers (control). All subjects were submitted to multivoxel proton magnetic resonance spectroscopic imaging. When compared to the control group, patients presented significantly lower NAA / (Cr + Cho) ratios in the right dorsolateral prefrontal cortex (schizophrenia = 0.95 ± 0.03; control = 1.12 ± 0.04) and in the right (schizophrenia = 0.88 ± 0.02; control = 0.94 ± 0.03) and left (schizophrenia = 0.84 ± 0.03; control = 0.94 ± 0.03) cingulates. These ratios did not differ between electrodermally responsive and non-responsive patients. When patients were divided into two groups: lower SCL (less than the mean SCL of the control group minus two standard deviations) and normal SCL (similar to the control group), the subgroup with a lower level of SCL showed a lower NAA / (Cr + Cho) ratio in the left cingulate (0.78 ± 0.05) than the controls (0.95 ± 0.02, P < 0.05) and the subgroup with normal SCL (0.88 ± 0.03, P < 0.05). There was a negative correlation between the NAA / (Cr + Cho) ratio in the left cingulate of patients with schizophrenia and the duration of the disease and years under medication. These data suggest the existence of a schizophrenic subgroup characterized by low SCL that could be a consequence of the lower neuronal viability observed in the left cingulate of these patients.

Cannabidiol, a Cannabis sativa constituent, as an antipsychotic drug

A high dose of delta9-tetrahydrocannabinol, the main Cannabis sativa (cannabis) component, induces anxiety and psychotic-like symptoms in healthy volunteers. These effects of delta9-tetrahydrocannabinol are significantly reduced by cannabidiol (CBD), a cannabis constituent which is devoid of the typical effects of the plant. This observation led us to suspect that CBD could have anxiolytic and/or antipsychotic actions. Studies in animal models and in healthy volunteers clearly suggest an anxiolytic-like effect of CBD. The antipsychotic-like properties of CBD have been investigated in animal models using behavioral and neurochemical techniques which suggested that CBD has a pharmacological profile similar to that of atypical antipsychotic drugs. The results of two studies on healthy volunteers using perception of binocular depth inversion and ketamine-induced psychotic symptoms supported the proposal of the antipsychotic-like properties of CBD. In addition, open case reports of schizophrenic patients treated with CBD and a preliminary report of a controlled clinical trial comparing CBD with an atypical antipsychotic drug have confirmed that this cannabinoid can be a safe and well-tolerated alternative treatment for schizophrenia. Future studies of CBD in other psychotic conditions such as bipolar disorder and comparative studies of its antipsychotic effects with those produced by clozapine in schizophrenic patients are clearly indicated.

The size and prevalence of the cavum septum pellucidum are normal in subjects with panic disorder

Panic disorder is thought to involve dysfunction in the septohippocampal system, and the presence of a cavum septum pellucidum might indicate the aberrant development of this system. We compared the prevalence and size of cavum septum pellucidum in 21 patients with panic disorder and in 21 healthy controls by magnetic resonance imaging. The length of the cavum septum pellucidum was measured by counting the number of consecutive 1-mm coronal slices in which it appeared. A cavum septum pellucidum of >6 mm in length was rated as large. There was no significant difference in the proportion of patients (16 of 21 or 76.2 percent) and controls (18 of 21 or 85.7 percent) with a cavum septum pellucidum (P = 0.35, Fisher's exact test, one-tailed), and no members of either group had a large cavum septum pellucidum. The mean cavum septum pellucidum rating in the patient and control groups was 1.81 (SD = 1.50) and 2.09 (SD = 1.51), respectively. There were also no significant differences between groups when we analyzed cavum septum pellucidum ratings as a continuous variable (U = 196.5; P = 0.54). Across all subjects there was a trend towards a higher prevalence of cavum septum pellucidum in males (100 percent, 10 of 10) than females (75 percent, 24 of 32; P = 0.09, Fisher's exact test, one-tailed). Thus, we conclude that, while panic disorder may involve septo-hippocampal dysfunction, it is not associated with an increased prevalence or size of the cavum septum pellucidum.

Diagnostic profile of inpatients as a determinant of length of stay in a general hospital psychiatric unit

The aim of this study was to determine if the diagnostic profile of inpatients of a psychiatric unit in a general hospital influences the length of stay. The results of a retrospective survey comprising the first 16 years of operation of the Psychiatric Unit of the Ribeiräo Preto General Hospital (PURP) showed that the progressive increase observed in the length of stay correlated with the increase in percentage of schizophrenia diagnosis, after the 8th year of hospital operation, and of affective disorders, after the 12th year. The length of hospitalization kept increasing until the 16th year, even though there was no change in the diagnostic profile of the patients admitted to the unit. In a prospective study encompassing the next six months, 61 inpatients were evaluated with the Structured Clinical Interview for DSM-III-R and the Brief Psychiatric Rating Scale (BPRS). The results showed that 82 percent of the inpatients fulfilled the diagnostic criteria for the schizophrenic or affective disorder spectrum at admission, with a discharge rate slower than for other diagnoses, although the length of hospitalization did not significantly differ among diagnostic categories. The results further demonstrated that in every diagnostic category more than 50 percent of the patients stayed in hospital for more than one week after reaching a BPRS score equal to 6, indicative of discharge. Overall, these data suggest that the increase in length of hospitalization may be due to a higher percentage of patients with a diagnosis of schizophrenia and affective disorder admitted to the PURP. In addition, patients with low symptomatic levels remained in hospital longer than they should have

Factor structure of Bech's version of the Brief Psychiatric Rating Scale in Brazilian patients

The objective of the present study was to evaluate the factor structure of Bech's version of the Brief Psychiatric Rating Scale (BPRS), translated into Portuguese. The BPRS was administered to a heterogeneous group of psychiatric inpatients (N = 98) and outpatients (N = 62) in a University Hospital. Each patient was evaluated from one to eight times. The interval between consecutive interviews was one week for the inpatients and one month for the outpatients. The results were submitted to factorial analysis. The internal consistency of the total scale and of each factor was also estimated. Factorial analysis followed by normalized orthogonal rotation (Varimax) yielded four factors: Withdrawal-Retardation, Thinking Disorder, Anxious-Depression and Activation. Internal consistency measured by Cronbach's alpha coefficient ranged from 0.766 to 0.879. The data show that the factor structure of the present instrument is similar to that of the American version of the BPRS which contains 18 items, except for the absence of the fifth factor of the latter scale, Hostile-Suspiciousness

Reliability and validity of the interactive observation scale for psychiatric inpatients applied by nursing aides in daily ward practice

The main characteristic of the nursing Interactive Observation Scale for Psychiatric Inpatients (IOSPI) is the necessity of interaction between raters and patients during assessment. The aim of this study was to evaluate the reliability and validity of the scale in the "real" world of daily ward practice and to determine whether the IOSPI can increase the interaction time between raters and patients and influence the raters' opinion about mental illness. All inpatients of a general university hospital psychiatric ward were assessed daily over a period of two months by 9 nursing aides during the morning and afternoon shifts, with 273 pairs of daily observations. Once a week the patients were interviewed by a psychiatrist who filled in the Brief Psychiatric Rating Scale (BPRS). The IOSPI total score was found to show significant test-retest reliability (interclass correlation coefficient = 0.83) and significant correlation with the BPRS total score (r = 0.69), meeting the criteria of concurrent validity. The instrument can also discriminate between patients in need of further inpatient treatment from those about to be discharged (negative predictive value for discharge = 0.91). Using this scale, the interaction time between nursing aides and patients increased significantly (t = 2.93, P<0.05) and their opinion about the mental illness changed. The "social restrictiveness" factor of the opinion scale about mental illness showed a significant reduction (t = 4.27, P<0.01) and the "interpersonal etiology" factor tended to increase (t = 1.98, P = 0.08). The IOSPI was confirmed as a reliable and valid scale and as an efficient tool to stimulate the therapeutic attitudes of the nursing staff

Effects of tryptophan depletion on anxiety induced by simulated public speaking

Several lines of evidence point to the participation of serotonin (5HT) in anxiety. Its specific role, however, remains obscure. The objective of the present study was to evaluate the effect of reducing 5HT-neurotransmission through an acute tryptophan depletion on anxiety induced by a simulated public speaking (SPS) test. Two groups of 14-15 subjects were submitted to a 24-h diet with a low or normal content of tryptophan and received an amino acid mixture without (TRY-) or with (TRY+) tryptophan under double-blind conditions. Five hours later they were submitted to the SPS test. The state-trait anxiety inventory (STAI) and the visual analogue mood scale (VAMS) were used to measure subjective anxiety. Both scales showed that SPS induced a significant increase in anxiety. Although no overall difference between groups was found, there was a trend (P = 0.078) to an interaction of group x gender x phases of the SPS, and a separate analysis of each gender showed an increase in anxiety measured by the STAI in females of the TRY- group. The results for the female TRY- group also suggested a greater arousing effect of the SPS test. In conclusion, the tryptophan depletion procedure employed in the present study did not induce a significant general change in subjective anxiety, but tended to induce anxiety in females. This suggests a greater sensitivity of the 5HT system to the effects of the procedure in this gender.

Reliability of the Portuguese version of the structured clinical interview for DSM-III-R (SCID) in a Brazilian sample of psychiatric outpatients

The objective of the present study was to determine the reliability psychiatric diagnoses using a translation and adaptation to Portuguese of the "Structured Clinical Interview for DSM-III-R - patient version" (SCID-P) and the "Structured Clinical Interview for DSM-III-R Personality Disorders" (SCID-II), using the joint interviews methodology. Thirty-nine subjects were evaluated using the SCID-P and 20 of them using the SCID-II. Interrater reliability was analyzed statistically by means of the Kappa Coefficient. Agreement between results obtained with SCID-P was statistically significant for the major diagnostic categories of DSM-III-R and for 10 of the 12 specific diagnostic categories studied (a minimum of 4 subjects per diagnosis). Agreement was not statistically significant for Psychotic Disorder Not. Otherwise Specified (NOS) and for Other Bipolar Disorder. The Weighted Kappa for the main diagnoses and the Overall Kappa for the entire set of 25 specific diagnostic categories proposed by the SCID-P were statistically significant. The general agreement for Personality Disorders with SCID-II was statistically significant. The Kappa Coefficient was determined for the Avoidant, Paranoid, Histrionic and Borderline Personality Disorders and for the Conduct Disorder. The remaining Personality Disorders were not analyzed statistically because of their low prevalence in the sample. Agreement was not significant only for the Histrionic Personality Disorder. These data suggest that the translation and adaptation of the SCID-P and SCID-II to Portuguese presents, in general, good reliability indices, and thus its use is recommended.

Anxiety induced by simulated public speaking and stroop color word test in healthy subjects: affects of different trait-anxiety levels

The objective of the present study was to compare the effects of two anxiety-inducing tests, simulated public speaking (SPS) and the stroop color word test (SCWT), in healthy subjects with different trait-anxiety levels. 2. The mean (+ or - SD) trait-anxiety score of 524 university students, measured by Spielberger's state-trait anxiety inventory (STAI), was 40.8 + or - 8.9. Based on these scores, 26 students from our sample were divided into low (score less than 1 SD from the mean, N = 10), medium (score between -1 and + 1 SD from the mean, N = 7) and high (score more than 1 SD from the mean, N = 9) trait anxiety. 3. Each subject was submitted to the SPS and SCWT tests in the same experimental session. The sequence of test presentation was randomized between subjects. No effect of test order presentation was found. 4. SPS induced significant increases in the anxiety factor of Norris' visual analogue mood scale (VAMS) in all groups, without difference between them. The SCWT, on the other hand, did not induce an increase in subjective anxiety in any group. In the high trait group, however, there was a general increase in anxiety feeling that was evident even before the test, and might have been caused by the presence of the experimenter. 5. The results suggest that SPS is a more effective anxiety-inducing test, and is not dependent on previous trait-anxiety levels

D-fenfluramine reduces anxiety induced by simulated public speaking

To further explore the role of serotonin (5-HT) in anxiety, 28 healthy volunteers received in a double-blind study d-fenfluramine (30 mg, p.o.) or placebo, and were submitted to a simulated public speaking test (SPS), consisting of speaking in front of a video camera. The SPS induced significant increases in subjective anxiety evaluated by the visual analogue mood scale of Norris [MANCOVA, F(1.66,39.93) = 8.51, P < 0.001], as well as in systolic blood pressure [F(3,72) = 5.70, P = 0.001] and in heart rate [F(3,72) = 3.95, P = 0.012]. The drug decreased the anxiety factor [F(1,23) = 5.21, P = 0.032], without significantly affecting physical sedation, mental sedation or other feelings and attitudes. Also, the physiological measurements were not significantly changed by d-fenfluramine. Reported evidence shows that d-fenfluramine releases 5-HT from nerve endings and blocks 5-HT reuptake, indirectly stimulating postsynaptic 5-HT receptors. Therefore, the present results indicate that 5-HT inhibits the neural substrate of SPS-induced anxiety

Effect of cannabidiol on plasma prolactin, growth hormone and cortisol in human volunteers

In the present study, we investigated the effects of cannabidiol (CBD) on plasma prolactin, growth hormone and cortisol of 11 normal volunteers who received placebo or CBD at the doses of 300 mg (N = 7) or 600 mg (N = 4), po, in a double-blind manner during two experimental sessions separated by an interval of at least one week. The sessions were held in the morning and consisted of blood collection and application of self-evaluation scales before and after drug injection (-35 to 180 min). Hormonal measurements were performed by radioimmunoassay. Basal prolactin (11.5 +/- 4.3 ng/ml) and growth hormone (1.5 +/- 0.7 ng/ml) levels were unchanged after placebo and CBD. In contrast, plasma cortisol levels decreased significantly during the placebo sessions (basal measurement = 11.0 +/- 3.7 micrograms/dl; 120 min after placebo = 7.1 +/- 3.9 micrograms/dl), in agreement with the normal circadian rhythm of this hormone. This decrease in cortisol levels was significantly attenuated after CBD (basal measurement = 10.5 +/- 4.9 micrograms/dl; 120 min after 300 mg CBD = 9.9 +/- 6.2 micrograms/dl; 120 min after 600 mg CBD = 11.6 +/- 11.6 micrograms/dl). CBD was also found to have a sedative effect as determined by the self-evaluation scales. The present results suggest that CBD interferes with cortisol secretion

A importância do treinamento prévio em escala analógica de auto-avaliaçäo / The importance of previous training in a self-rating analogue scale

A aplicaçäo no nosso meio de uma traduçäo da escala analógica de humor (Visual Analogue Mood Scale) produziu distribuiçäo de escores concentrados nas extremidades da escala ao invés da distribuiçäo normal encontrada originalmente por BOND e LADER (1974). Isto poderia ter sido devido a erros de interpretaçäo das instruçöes escritas. Foi sugerido que um treinamento prévio no preenchimento desta escala poderia melhorar sua confiabilidade e normalizar a distribuiçäo de escores. Neste trabalho comparamos a distribuiçäo de escores de dois grupos de voluntários, com e sem treinamento prévio, no uso da escala. Os resultados mostram que os escores do grupo que realizou o treinamento prévio apresentam uma distribuiçäo que se aproxima da normalidade, enquanto o grupo sem treinamento tem seus escores distribuídos nas extremidades da escala. Isto confirma que o treinamento prévio no preenchimento desta escala analógica é importante e contribui para o seu melhor uso

Interacao farmacologica entre delta9 tetrahidrocanabinol e o canabidiol, dois constituintes ativos da Cannabis sativa. / Pharmacological interection between tetrahydrocannabinol and cannabidiol, 2 active constituents of Cannabis sativa

Apesar do delta9 trans tetrahidrocanabinol (Delta9 THC) ser comumente aceito como o principal constituinte ativo da Cannabis sativa, relatos recentes tem demonstrado que o canabidiol (CBD), outro constituinte da planta, influencia a atividade farmacologica do Delta9 THC em animais e no homem. Diferentes grupos tem estudado a interacao entre o Delta9 THC e o CBD com resultados aparentemente contraditorios. Os autores discutem neste artigo, no qual sao incluidos seus trabalhos previos, a imporancia dos provaveis mecanismos farmacocineticos e farmacodinamicos que influenciam a interacao complexa entre essas duas drogas

Relacao droga-doenca em patologia mental. / The relationship between drug abuse and mental pathology

O possivel relacionamento entre doenca mental e o uso ou abuso de drogas psicotropicas e muito complexo envolvendo a interferencia de inumeras variaveis. Neste trabalho, os autores discutem o problema, trazendo a experiencia adquirida pela realizacao de investigacoes, onde uma possivel relacao entre sintomas como depressao ou ansiedade e o uso de alcool e canabis e enfocada

Estudo duplo-cego sobre a acao de L-dopa em pacientes psicoticos con discinesia tardia. / A double-blind study on the effect of L-dopa in psychotic patients tardive dyskinesia

A manipulacao adequada de sistemas dopaminergicos, que provavelmente contribuem para a Discinesia tardia, pode levar a uma diminuicao da intensidade da mesma. Assim, em pacientes psiquiatricos, com a sintomatologia psicotica estabilizada, e com Discinesia tardia, a administracao de L-dopa, que se transforma em dopamina no SNC, em diversas doses, nao muito altas, em condicoes de duplo-cego, por um periodo longo, onde a quantidade de substancia ingerida era aumentada gradativamente, levou com uma das doses, 1 grama diaria, a uma diminuicao significante da intensidade dos movimentos involuntarios, em relacao a um grupo controle que recebia placebo

Estudo transcultural de uma escala de auto-avaliacao para estados subjetivos. / Transcultural study of a self-rating scale for subjective states

As escalas desenvolvidas em outras linguas e culturas encontram dificuldades de adaptacao para o nosso meio. Traduziu-se para o portugues a escala de Norris e replicou-se em universitarios brasileiros o teste feito por Bond & Lader. Sao discutidas as diferencas encontradas entre os dois estudos