Antenatal exposure to antidepressant drugs and the risk of neurodevelopmental and psychiatric disorders: a systematic review / Exposição intrauterina a antidepressivos e risco de transtornos de neurodesenvolvimento e psiquiátricos: uma revisão sistemática / Exposición prenatal a medicamentos antidepresivos y riesgo de trastornos psiquiátricos y en el desarrollo neurológico: una revisión sistemática

Abstract: This study investigated whether antenatal exposure to antidepressants (ADs) increases the risks of autism spectrum disorders (ASD), attention deficit/hyperactivity disorders (ADHD), schizophrenia and other mental illnesses, and cognitive and developmental deficits in infants or preschool children. PubMed, EMBASE, BIREME/BVS databases were searched to identify studies examining associations of ADs in pregnancy with neurodevelopmental and psychiatric disorders. Twenty studies addressed ASD and/or ADHD risks while 30 focused on developmental and cognitive deficits in infants or preschool children. Most studies detected no association of antenatal AD with ASD after adjustment of risk ratios for maternal depression or psychiatric disorders. Some studies showed that maternal depression, regardless of whether it is treated or untreated, increased ASD risks. Seven out of 8 studies found no increase in ADHD risk associated with antenatal exposure to selective serotonin reuptake inhibitors, the most commonly used AD. No consistent evidence was found linking AD in pregnancy to neurocognitive developmental deficits in infants or preschool children. A residual confounding by indication (depression severity) remained in almost all studies. This systematic review found no consistent evidence suggesting that ADs in pregnancy increase risks of ASD, ADHD, and neurocognitive development deficits. Some studies, however, found evidence that maternal depression increases ASD risks.

Resumo: O estudo teve como objetivo investigar se a exposição intrauterina a antidepressivos (ADs) aumenta o risco de transtornos do espectro autista (TEA), transtorno de déficit de atenção e hiperatividade (TDAH), esquizofrenia e outros transtornos mentais e déficits cognitivos e de desenvolvimento em lactentes e pré-escolares. Foram realizadas buscas nas bases PubMed, EMBASE e BIREME/BVS para identificar estudos sobre associações entre o uso de ADs durante a gestação e transtornos de neurodesenvolvimento e psiquiátricos. Vinte estudos trataram de riscos de TEA e/ou TDAH, enquanto 30 focaram em déficits cognitivos e de desenvolvimento em lactentes ou pré-escolares. A maioria dos estudos não detectou associação entre AD na gestação e TEA, depois de ajustar as razões de risco para depressão ou outros transtornos psiquiátricos maternos. Alguns estudos mostraram que a depressão materna, quer tratada ou não, aumenta o risco de TEA. Sete entre oito estudos não detectaram aumento de risco de TDAH associado à exposição intrauterina a inibidores seletivos da recaptação da serotonina, o AD mais comumente utilizado. Não foram encontradas evidências consistentes entre o uso de AD na gestação e déficits de desenvolvimento neurocognitivo em lactentes ou pré-escolares. Em quase todos os estudos, permaneceu um confundimento residual por indicação (gravidade da depressão). A revisão sistemática não encontrou evidências consistentes de que os ADs na gestação aumentassem o risco de TEA, TDAH ou déficits de desenvolvimento neurocognitivo. Entretanto, alguns estudos evidenciaram que a depressão materna aumenta o risco de TEA.

Resumen: Este estudio investigó si la exposición prenatal a antidepresivos (ADs) incrementa los riesgos de trastornos del espectro autista (TEA), trastornos de déficit de atención/hiperactividad (TDAH), esquizofrenia, así como otras enfermedades mentales, cognitivas, y déficits en el desarrollo de niños de primaria o preescolares. Se consultaron las bases de datos PubMed, EMBASE, BIREME/BVS para identificar estudios de asociaciones de ADs durante el embarazo con trastornos de desarrollo neurológico y psiquiátricos. Veinte estudios estaban centrados en riesgos de TEA y/o TDAH, mientras que 30 se centraron en déficits de desarrollo y cognitivos en niños de primaria o preescolares. La mayor parte de los estudios no detectaron asociación de AD, durante la etapa prenatal, con TDA tras el ajuste de las ratios de riesgo para depresión materna o trastornos psiquiátricos. Algunos estudios mostraron que la depresión materna, independientemente de si es tratada o no, incrementó los riesgos de TEA. Siete de los 8 estudios no encontraron un incremento en el riesgo de TDAH, asociado con la exposición prenatal a inhibidores selectivos de la recaptación de serotonina, el antidepresivo más usado habitualmente durante el período prenatal. No se encontraron evidencias consistentes relacionando AD durante el embarazo y déficits en el desarrollo neurocognitivo de niños de primaria o preescolares. En casi todos los estudios hubo una desviación residual señalada como gravedad de la depresión. Esta revisión sistemática no halló evidencias consistentes, sugiriendo que el consumo de ADs durante el embarazo incremente el riesgo de TEA, TDAH, y déficits en el desarrollo neurocognitivo. Algunos estudios, no obstante, encontraron evidencias de que la depresión materna incrementa riesgos de TEA.

Is Forced Swimming Immobility a Good Endpoint for Modeling Negative Symptoms of Schizophrenia? - Study of Sub-Anesthetic Ketamine Repeated Administration Effects

ABSTRACT Immobility time in the forced swimming has been described as analogous to emotional blunting or apathy and has been used for characterizing schizophrenia animal models. Several clinical studies support the use of NMDA receptor antagonists to model schizophrenia in rodents. Some works describe the effects of ketamine on immobility behavior but there is variability in the experimental design used leading to controversial results. In this study, we evaluated the effects of repeated administration of ketamine sub-anesthetic doses in forced swimming, locomotion in response to novelty and novel object recognition, aiming a broader evaluation of the usefulness of this experimental approach for modeling schizophrenia in mice. Ketamine (30 mg/kg/day i.p. for 14 days) induced a not persistent decrease in immobility time, detected 24h but not 72h after treatment. This same administration protocol induced a deficit in novel object recognition. No change was observed in mice locomotion. Our results confirm that repeated administration of sub-anesthetic doses of ketamine is useful in modeling schizophrenia-related behavioral changes in mice. However, the immobility time during forced swimming does not seem to be a good endpoint to evaluate the modeling of negative symptoms in NMDAR antagonist animal models of schizophrenia.

Cannabis y esquizofrenia. Revisión de la literatura de los últimos quince años / Cannabis and schizophrenia. Review of the literature of the last fifteen years

A partir de la promulgación de la Ley 19.172, referida a la regulación del mercado y consumo de marihuana, recientemente aprobada en Uruguay, surgen diferentes preguntas en relación con los efectos de esta norma sobre los pacientes psiquiátricos con un trastorno por consumo de cannabis comórbido, particularmente en el caso de la comorbilidad con esquizofrenia. La prevalencia de la esquizofrenia en la población general es de 0.5 a 1.4 %, con una comorbilidad con consumo de sustancias de aproximadamente el 47 % que, en el caso del consumo de cannabis, oscila entre 13 y 40 %. Los avances en la neurobiología apuntan a una compleja relación entre el sistema endocannabinoide, la esquizofrenia y los cannabinoides exógenos. Los objetivos son conocer, a través de la revisión de la literatura internacional, los avances en cuanto al vínculo entre el cannabis y la esquizofrenia tanto desde el punto de visto clínico como neurobiológico. Se encontraron 130 trabajos con los descriptores utilizados, de los cuales se seleccionaron para este trabajo los 35 de mayor relevancia. El consumo de cannabis podría ser un factor de riesgo para individuos vulnerables a la psicosis. Tendría además un efecto sobre la edad de inicio de la enfermedad y, posiblemente, en su evolución.

Since the enactment of Law 19,172, referring to the regulation of the marijuana market and consumption, recently approved in Uruguay, different questions arise regarding the effects of this rule on psychiatric patients with comorbid cannabis use disorder, particularly in the case of comorbidity with schizophrenia. The prevalence of schizophrenia in the general population is 0.5 to 1.4%, with a comorbidity with substance use of approximately 47% which, in the case of cannabis use, ranges between 13 and 40%. Advances in neurobiology point to a complex relationship between the endocannabinoid system, schizophrenia and exogenous cannabinoids. The objectives are to know, through the review of the international literature, the advances regarding the link between cannabis and schizophrenia both from the clinical and neurobiological point of view. We found 130 papers with the descriptors used, of which the 35 most relevant ones were selected for this work. Cannabis use could be a risk factor for individuals vulnerable to psychosis. It would also have an effect on the age of onset of the disease and, possibly, on its evolution.

Sex-dependent behavioral effects and morphological changes in the hippocampus after prenatal invasive interventions in rats: implications for animal models of schizophrenia

OBJECTIVES: Although schizophrenia affects both human genders, there are gender-dependent differences with respect to age of onset, clinical characteristics, course and prognosis of the disease. METHODS: To investigate sex-dependent differences in motor coordination and activity as well as in cognitive and social behavior, we repeatedly tested female (n = 14) and male (n = 12) Fisher rats (postnatal days, PD 56-174) that had received intracerebroventricular injections of kainic acid as well as female (n = 15) and male (n = 16) control animals. The hippocampus was examined histologically. RESULTS: Compared to male controls, in the alcove test both female controls and female animals with prenatal intervention spent less time in a dark box before entering an unknown illuminated area. Again, animals that received prenatal injection (particularly females) made more perseveration errors in the T-maze alternation task compared to controls. Female rats exhibited a higher degree of activity than males, suggesting these effects to be sex-dependent. Finally, animals that received prenatal intervention maintained longer lasting social contacts. Histological analyses showed pyramidal cells in the hippocampal area CA3 (in both hemispheres) of control animals to be longer than those found in treated animals. Sex-dependent differences were found in the left hippocampi of control animals and animals after prenatal intervention. CONCLUSION: These results demonstrate important differences between males and females in terms of weight gain, response to fear, working memory and social behavior. We also found sex-dependent differences in the lengths of hippocampal neurons. Further studies on larger sample sets with more detailed analyses of morphological changes are required to confirm our data.

El modelo de la fenciclidina en la esquizofrenia / The phencyclidine model of schizophrenia

La fenciclidina (PCP) produce psicosis muy similares a la esquizofrenia. Mientras las psicosis inducidas por anfetamina presentan sólo síntomas positivos como delirio y alucinaciones, las psicosis inducidas por PCP presentan tanto síntomas positivos como negativos (aplanamiento afectivo, retardo psicomotor, empobrecimiento del discurso). De este modo las psicosis anfetamínicas se ajustan a un modelo schneideriano y las psicosis por PCP a un modelo bleuleriano de esquizofrenia. La PCP se une selectivamente a un sitio de unión específico, el receptor a aminoácidos excitatorios N-metil-D-aspaertato (NMDA). Estos hallazgos sugieren que una disfunción de la neurotransmisión mediada por el receptor NMDA puede contribuir a la etiopatogenia de la esquizofrenia