ABSTRACT
Deep brain stimulation (DBS) in the subgenual cingulated gyrus (SCG) is a promising new technique that may provide sustained remission in resistant major depressive disorder (MDD). Initial studies reported a significant early improvement in patients, followed by a decline within the first month of treatment, an unexpected phenomenon attributed to potential placebo effects or a physiological response to probe insertion that remains poorly understood. Here we characterized the behavioural antidepressant-like effect of DBS in the rat medial prefrontal cortex, focusing on modifications to rodent SCG correlate (prelimbic and infralimbic (IL) cortex). In addition, we evaluated the early outcome of DBS in the SCG of eight patients with resistant MDD involved in a clinical trial. We found similar antidepressant-like effects in rats implanted with electrodes, irrespective of whether they received electrical brain stimulation or not. This effect was due to regional inflammation, as it was temporally correlated with an increase of glial-fibrillary-acidic-protein immunoreactivity, and it was blocked by anti-inflammatory drugs. Indeed, inflammatory mediators and neuronal p11 expression also changed. Furthermore, a retrospective study indicated that the early response of MDD patients subjected to DBS was poorer when they received anti-inflammatory drugs. Our study demonstrates that electrode implantation up to the IL cortex is sufficient to produce an antidepressant-like effect of a similar magnitude to that observed in rats receiving brain stimulation. Moreover, both preclinical and clinical findings suggest that the use of anti-inflammatory drugs after electrode implantation may attenuate the early anti-depressive response in patients who are subjected to DBS.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Cerebral Cortex/drug effects , Cerebral Cortex/physiopathology , Deep Brain Stimulation , Depressive Disorder, Major/physiopathology , Depressive Disorder, Major/therapy , Animals , Chronic Disease , Deep Brain Stimulation/adverse effects , Disease Models, Animal , Female , Glial Fibrillary Acidic Protein/metabolism , Gyrus Cinguli/drug effects , Gyrus Cinguli/physiopathology , Humans , Male , Neuroimmunomodulation/drug effects , Neuroimmunomodulation/physiology , Rats, Wistar , Retrospective Studies , Stress, Psychological , Treatment OutcomeABSTRACT
BACKGROUND AND PURPOSE: The antidepressant efficacy of selective 5-HT reuptake inhibitors (SSRI) and other 5-HT-enhancing drugs is compromised by a negative feedback mechanism involving 5-HT(1A) autoreceptor activation by the excess 5-HT produced by these drugs in the somatodendritic region of 5-HT neurones. 5-HT(1A) receptor antagonists augment antidepressant-like effects in rodents by preventing this negative feedback, and the mixed ß-adrenoceptor/5-HT(1A) receptor antagonist pindolol improves clinical antidepressant effects by preferentially interacting with 5-HT(1A) autoreceptors. However, it is unclear whether 5-HT(1A) receptor antagonists not discriminating between pre- and post-synaptic 5-HT(1A) receptors would be clinically effective. EXPERIMENTAL APPROACH: We characterized the pharmacological properties of the 5-HT(1A) receptor antagonist DU-125530 using receptor autoradiography, intracerebral microdialysis and electrophysiological recordings. Its capacity to accelerate/enhance the clinical effects of fluoxetine was assessed in a double-blind, randomized, 6 week placebo-controlled trial in 50 patients with major depression (clinicaltrials.gov identifier NCT01119430). KEY RESULTS: DU-125530 showed equal (low nM) potency to displace agonist and antagonist binding to pre- and post-synaptic 5-HT(1A) receptors in rat and human brain. It antagonized suppression of 5-hydroxytryptaminergic activity evoked by 8-OH-DPAT and SSRIs in vivo. DU-125530 augmented SSRI-induced increases in extracellular 5-HT as effectively as in mice lacking 5-HT(1A) receptors, indicating a silent, maximal occupancy of pre-synaptic 5-HT(1A) receptors at the dose used. However, DU-125530 addition to fluoxetine did not accelerate nor augment its antidepressant effects. CONCLUSIONS AND IMPLICATIONS: DU-125530 is an excellent pre- and post-synaptic 5-HT(1A) receptor antagonist. However, blockade of post-synaptic 5- HT(1A) receptors by DU-125530 cancels benefits obtained by enhancing pre-synaptic 5-hydroxytryptaminergic function.
Subject(s)
Antidepressive Agents/administration & dosage , Depressive Disorder, Major/drug therapy , Fluoxetine/administration & dosage , Piperazines/administration & dosage , Receptor, Serotonin, 5-HT1A/physiology , Serotonin Antagonists/administration & dosage , Thiazoles/administration & dosage , 8-Hydroxy-2-(di-n-propylamino)tetralin/pharmacology , Adult , Animals , Brain/drug effects , Brain/physiology , Drug Therapy, Combination , Female , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Middle Aged , Piperazines/pharmacology , Pyridines/pharmacology , Rats , Rats, Wistar , Serotonin Receptor Agonists/pharmacologyABSTRACT
La estimulación cerebral profunda (ECP) es un técnica invasiva y reversible instaurada en los últimos tiempos para el tratamiento de enfermedades neurológicas y psiquiátricas. Si nos centramos en su uso en psiquiatría, se han publicado hasta la actualidad diferentes trabajos con buenos resultados en trastorno obsesivo compulsivo, en el trastorno de ansiedad generalizada y en el trastorno depresivo mayor recurrente (TDM). En el Hospital de Sant Pau de Barcelona hemos realizado un estudio aleatorizado, cruzado y doble ciego de ECP en 8 pacientes con TDM resistente a múltiples tratamientos, utilizando la ECP bilateral en el área subcallosa del cíngulo o área Cg25. Tras un año de seguimiento, en este estudio hemos obtenido unos resultados esperanzadores: 87 % de respuesta y 70 % de remisión clínica, sin que los pacientes presentaran efectos secundarios remarcables. Centrándonos en el uso de la ECP en adicciones, hay muy poco publicado, y casi todos los estudios son preclínicos. Nombraremos algunos de ellos, así como varios de los artículos que hay publicados en humanos, y abriremos una puerta a la futura investigación de técnicas invasivas que incidan en el circuito de recompensa y puedan así ayudar a controlar el craving de los pacientes con problemas adictivos (AU)
Deep brain stimulation (DBS) is an invasive and reversible technique recently introduced in the treatment of neurological and psychiatric diseases. To date, there have been published different jobs in psychiatry with good results in OCD, MDD and GAD. In our centre, (Hospital de Sant Pau, in Barcelona), we have made a randomized, double-blind and crossover study in 8 patients with MDD resistant to multiple treatments, using bilateral DBS in the subgenual area or Cg25. We obtained after 1 year follow up encouraging results: 87 % response and 70 % of clinical remission, with unimportant side effects. Focusing on the use of ECP in addictions, there is very little published, and almost all studies are preclinical. We'll give some data about some of them, as well as 2 of the articles that have been published in humans. This may open the door to future research on invasive techniques that affect the reward circuitry, and give the key to control craving in addictive disorders (AU)
Subject(s)
Humans , Male , Adult , Middle Aged , Deep Brain Stimulation/instrumentation , Deep Brain Stimulation/methods , Substance-Related Disorders/psychology , Depression/complications , Depression/psychology , Nucleus Accumbens/metabolism , Subthalamic Nucleus/metabolism , Deep Brain Stimulation/classification , Deep Brain Stimulation/psychology , Deep Brain Stimulation/trends , Electric Stimulation/methods , Reward , Gyrus Cinguli/blood supply , Gyrus Cinguli/metabolismABSTRACT
Introducción: Estudio prospectivo de 5 años, cuyo objetivo es evaluar la estabilidad temporal del diagnóstico de trastorno esquizofreniforme (TE) provisional y evaluar la validez predictiva de las características de buen pronóstico que define el Manual Diagnóstico y Estadístico de los Trastornos Mentales (DSM-IV). Sujetos y métodos: La muestra consta de 38 pacientes (23 varones y 15 mujeres) ingresados en el hospital, entre 1996 y 1998, por un primer episodio psicótico. Se realizaron 4 entrevistas de seguimiento: en el primer, segundo, tercer y quinto años. Los pacientes se evaluaron mediante la Brief Psychiatric Rating Scale (BPRS), la Escala de Evolución de Strauss-Carpenter, la entrevista clínica estructurada del DSM-IV (SCID) y la Escala de Evaluación de la Actividad Global (EEAG). Resultados: Completaron el seguimiento de 5 años 27 pacientes. El 25,9% mantenía el diagnóstico de TE a los 5 años y el 59,2% se clasificaron dentro del espectro esquizofrénico. La presencia en el primer ingreso de características de buen pronóstico se asoció con una mejor evolución a los 5 años, pero no se asoció al mantenimiento del diagnóstico de TE. Los pacientes que mantuvieron el diagnóstico de TE presentaron mejor evolución que los pacientes esquizofrénicos. Conclusiones: Tras 5 años de seguimiento, la mayoría de los pacientes continúan presentando síntomas y cumplen criterios de esquizofrenia o trastorno esquizoafectivo, lo que confirma la baja estabilidad del diagnóstico TE. Los hallazgos sugieren una asociación entre las características de buen pronóstico y una mejor evolución, aunque no se observa asociación con el mantenimiento del diagnóstico TE
Introduction: We performed a 5-year prospective study to evaluate the temporal stability of a provisional diagnosis of schizophreniform disorder (SFD) and evaluate the predictive value of the good prognostic features defined in the DSM-IV. Subjects and Methods: The sample consisted of 38 patients (23 men and 15 women) admitted to our hospital from 1996 to 1998 for a first psychotic episode. Four follow-up interviews were obtained: at the first, second, third and fifth years of follow-up. Patients were evaluated by means of the Brief Psychiatric Rating Scale (BPRS), the Strauss-Carpenter Scale, the Structured Clinical Interview of the DSM-IV (SCID) and the Global Assessment of Functioning Scale (GAF Scale) of the DSM-IV. Results: Twenty-seven patients completed the study. A total of 25.9% retained the diagnosis of SFD and 59.2% were classified as having a disorder of the schizophrenic spectrum. The presence of good prognostic features at the index admission was associated with better outcome, but not with maintenance of the diagnosis of SFD. After 5 years of follow-up, patients with SFD showed significantly better outcomes than did schizophrenic patients. Conclusions: After 5 years of follow-up most of the patients continued to have symptoms and met the criteria for schizophrenia or schizoaffective disorder, confirming the low stability of a provisional diagnosis of SFD. The results of this study suggest an association between good prognostic features and better outcome, but not with maintenance of a diagnosis of SFD
