Trastorno límite de la personalidad (TLP): características, etiología y tratamiento / Borderline personality disorder (BPD): features, etiology and treatment

El trastorno límite de personalidad (TLP) se ha considerado como el paradigma de trastorno severo de la personalidad. Los principales síntomas son el comportamiento suicida, la autolesión no suicida, el comportamiento agresivo y la reactividad emocional. El inicio del TLP depende de la combinación de factores genéticos y ambientales, especialmente de la vulnerabilidad biológica y la exposición a experiencias traumáticas durante la infancia. Entre sus características destacan las alteraciones en la percepción de posibles amenazas y rechazo social, las interacciones emoción-cognición y alteraciones de la cognición social, la importancia del estrés social y la mentalización. En el aspecto neurobiológico destacan alteraciones del volumen de diversas estructuras cerebrales, metabolismo cerebral, alteraciones funcionales y de la conectividad funcional. Los trastornos psiquiátricos comórbidos más frecuentes en los pacientes con TLP son ansiedad, trastornos afectivos, trastorno por déficit de atención e hiperactividad, trastorno de estrés postraumático y abuso de sustancias. En lo que se refiere al tratamiento, destacan las técnicas psicológicas, como la terapia conductual dialéctica y la EMDR, pero es frecuente la utilización de fármacos eficaces para síntomas específicos, como agresividad/hostilidad o falta de control de los impulsos

Borderline personality disorder (BPD) is considered the most severe personality disorder. Principal symptoms are suicidal behavior, non-suicidal injuries, aggressive behavior and emotional hyperreactivity. BPD onset depends of the combination of genetics and environmental factors, specially on biological vulnerability and exposition to traumatic experiences during childhood. The main features are threatened feelings, social rejection, interactions emotion-cognition and social cognition disorders, social stress and mentalization difficulties. About neurobiological aspects, we can highlight disorders in brain structures, brain metabolism, functional and functional connectivity. The most common comobird deseases in pacients with BPD are anxiety, affective disorders, attention deficit and hiperactivity disorder (ADHD), post traumatic stress disorder (PTSD) and substance abuse. According to treatment, psychological techniques are employed such as dialectical behavioral technique, EMDR. Usually, we can also associate drugs for controlling specific symptoms such as aggressivity o impulse control disabilities

Relationship between craving and impulsivity in patients with alcohol dependence with or without dual disorders in an outpatient treatment center: a descriptive study.

OBJECTIVES: To compare alcohol and other drugs abuse, state impulsivity, craving and the relationship between craving and impulsivity in alcohol-dependent patients with or without dual disorder attending to an alcohol treatment center in Cadiz town. METHOD: An observational, descriptive and transversal study performed on 112 alcohol dependent patient sample who were seeking treatment in ARCA outpatient treatment center in Cadiz. The sample was divided in two groups, according to present dual diagnosis or not. The sample was assessed with an AdHoc sociodemographic and clinical questionnaire and specific scales and interviews that included: 5.0 Mini International Neuropsychiatric Interview results (MINI), State Impulsivity Scale (SIS), and Multidimensional Alcohol Craving Scale (MACS). RESULTS: The prevalence of dual diagnosis was 50%, being the most prevalent disorders: Current and recurrent Major Depressive Episode Mood Disorder, Current Dysthymic Mood Disorder, Panic Disorder and Anxiety Disorder. 52,7% of the total sample had a positive result on the State Impulsivity Scale. No statistically significant results were found on the Craving Scale (neither in the score or in the sub-sections). A relationship between craving and impulsivity were found for all groups and researched items. CONCLUSIONS: As a relationship between craving and impulsivity was observed, these aspects should be considered as main factors for the treatment and evolution of alcohol- dependent patients.

Relación entre craving e impulsividad en pacientes con dependencia alcohólica con o sin patología dual en tratamiento ambulatorio: un estudio descriptivo / elationship between craving and impulsivity in patients with alcohol dependence with or without dual disorders in an outpatient treatment center: a descriptive study

Introducción: Comparar el consumo de alcohol y otras drogas, la impulsividad estado, el craving y la relación entre estos últimos en pacientes con dependencia alcohólica con o sin patología dual que acuden a un centro de tratamiento específico de alcoholismo en la ciudad de Cádiz. Metodología. Estudio observacional, descriptivo y transversal de una muestra de 112 pacientes con dependencia alcohólica que acuden para solicitar tratamiento al Centro de Tratamiento Ambulatorio ARCA, de Cádiz. Se divide a los pacientes en dos grupos, según padezcan o no patología dual, mediante la entrevista MINI 5.0. Se evalúa la impulsividad mediante la Escala de Impulsividad de Estado (EIE) y el craving mediante la Escala Multidimensional de Craving de Alcohol (EMCA) y se rellena un cuestionario de información adicional que recoge datos sociobiográficos, educativos, económicos y relativos al consumo de alcohol y otras drogas. Resultados. La prevalencia de patología dual es del 50%, las patologías más prevalentes son: Episodio Depre-sivo Mayor actual y recurrente, Trastorno Distímico actual, Trastorno de Angustia y Trastorno de Ansiedad. El 52,7% de la muestra global presenta un resultado positivo en la escala EIE. No existen diferencias de puntuación significativas, tanto en la valoración global como en los subapartados de la escala de craving. Existe una asociación entre el craving y la impulsividad en todos los subgrupos de población y en todas las categorías. Conclusiones. Existe una relación entre craving e impulsividad, lo que debe ser tenido en cuenta en el momento e planificar el tratamiento y diseñar estrategias de prevención de recaídas

Objectives: To compare alcohol and other drugs abuse, state impulsivity, craving and the relationship between craving and impulsivity in alcohol-dependent patients with or without dual disorder attending to an alcohol treatment center in Cadiz town. Method. An observational, descriptive and transversal study performed on 112 alcohol dependent patient sample who were seeking treatment in ARCA outpatient treatment center in Cadiz. The sample was divided in two groups, ac-cording to present dual diagnosis or not. The sample was assessed with an AdHoc sociodemographic and clinical questionnaire and specific scales and interviews that included: 5.0 Mini International Neuropsychiatric Interview results (MINI), State Impulsivity Scale (SIS), and Multidimensional Alcohol Craving Scale (MACS). Results. The prevalence of dual diagnosis was 50%, be-ing the most prevalent disorders: Current and recurrent Ma-jor Depressive Episode Mood Disorder, Current Dysthymic Mood Disorder, Panic Disorder and Anxiety Disorder. 52,7% of the total sample had a positive result on the State Impulsivity Scale. No statistically significant results were found on the Craving Scale (neither in the score or in the subsecions). A relationship between craving and impulsivity were found for all groups and researched items. Conclusions. As a relationship between craving and impulsivity was observed, these aspects should be considered as main factors for the treatment and evolution of alcohol-dependent patients

Fármacos glutamatérgicos en tratamiento de la esquizofrenia / Glutamatergic drugs for schizophrenia treatment

Actualmente se considera que tanto los síntomas positivos como en negativos de la esquizofrenia podrían deberse a una hipofunción glutamatérgica que tendría como consecuencia la alteración de la actividad de la neurotransmisión dopaminérgica. Concretamente, podría haber una disminución de la señalización glutamatérgica a nivel de los receptores NMDA, pero los agonistas directos de estos receptores no tienen utilidad clínica por ser inespecíficos y sus muchos efectos indeseables. Dados los problemas de falta de eficacia o de efectos secundarios que presentan los fármacos que actúan directamentesobre los receptores ionotrópicos y mGlu2-3, se han ensayado otros que actúan por otros mecanismos, especialmente indirectos, como es la administración co-agonistas de los receptores NMDA (glicina o D-serina), inhibidores del transportador de la glicina (sarcosina, Bitopertin), AMPAkinas (CX-516) y agonistas de los receptores mGlu5. Sin embargo, a pesar de los constantes fracasos, el enfoque glutamatérgico en el tratamiento de la esquizofrenia no está agotado y es necesario revisar todos los aspectos teóricos que relacionan estos mecanismos neuroquímicos con la compleja sintomatología esta patología hasta que logremos moléculas que sean realmente eficaces y que tengan un perfil de efectos secundarios aceptable

It is accepted that both positive and negative symptoms of schizophrenia may be due to hypofunction of glutamatergic pathways leading to altered dopaminergic neurotransmission activity. Specifically, there may be diminished glutamatergic signaling at the level of the NMDA receptors, but direct receptor agonists have no clinical utility due to their nonspecific actions and undesirable side effects. Given the problems of ineffectiveness or side effects of drugs that act directly on ionotropic and metabotropicmGlu2-3 receptors, clinical trials have been conducted with other drugs that have other mechanisms of action, especially indirect mechanisms, such as the co-administration of NMDA agonists (glycine or D-serine), glycine transporter inhibitors (sarcosine bitopertin), ampakines (CX-516), andmGlu5 receptor agonists. However, despite repeated failures, the glutamatergic approach to the treatment of schizophrenia has not been exhausted and all theoretical aspects that relate these complex neurochemical mechanisms with symptoms of schizophrenia should be reviewed until we find truly effective molecules with an acceptable side effect profile

Glutamatergic drugs for schizophrenia treatment.

It is accepted that both positive and negative symptoms of schizophrenia may be due to hypofunction of glutamatergic pathways leading to altered dopaminergic neurotransmission activity. Specifically, there may be diminished glutamatergic signaling at the level of the NMDA receptors, but direct receptor agonists have no clinical utility due to their nonspecific actions and undesirable side effects. Given the problems of ineffectiveness or side effects of drugs that act directly on ionotropic and metabotropic mGlu2-3 receptors, clinical trials have been conducted with other drugs that have other mechanisms of action, especially indirect mechanisms, such as the co-administration of NMDA agonists (glycine or D-serine), glycine transporter inhibitors (sarcosine bitopertin), ampakines (CX-516), and mGlu5 receptor agonists. However, despite repeated failures, the glutamatergic approach to the treatment of schizophrenia has not been exhausted and all theoretical aspects that relate these complex neurochemical mechanisms with symptoms of schizophrenia should be reviewed until we find truly effective molecules with an acceptable side effect profile.

Reduced antioxidant defense in early onset first-episode psychosis: a case-control study.

BACKGROUND: Our objective is to determine the activity of the antioxidant defense system at admission in patients with early onset first psychotic episodes compared with a control group. METHODS: Total antioxidant status (TAS) and lipid peroxidation (LOOH) were determined in plasma. Enzyme activities and total glutathione levels were determined in erythrocytes in 102 children and adolescents with a first psychotic episode and 98 healthy controls. RESULTS: A decrease in antioxidant defense was found in patients, measured as decreased TAS and glutathione levels. Lipid damage (LOOH) and glutathione peroxidase activity was higher in patients than controls. Our study shows a decrease in the antioxidant defense system in early onset first episode psychotic patients. CONCLUSIONS: Glutathione deficit seems to be implicated in psychosis, and may be an important indirect biomarker of oxidative stress in early-onset schizophrenia. Oxidative damage is present in these patients, and may contribute to its pathophysiology.

Role of atypical opiates in OCD. Experimental approach through the study of 5-HT(2A/C) receptor-mediated behavior.

RATIONALE: The selective serotonin (5-HT) reuptake inhibitors (SSRIs) represent the first-line pharmacotherapy for obsessive-compulsive disorder (OCD), and atypical antipsychotic drugs, which block 5-HT2A receptors, are used in augmentation strategies. Opiate drugs are also effective in treatment-refractory OCD and Tourette syndrome. The 5-HT2A-related behavior (i.e., head twitch) has been related with tics, stereotypes, and compulsive symptoms observed in Tourette syndrome and OCD. OBJECTIVES: The aim of this study was to explore whether 5-HT2A-related behavior is affected by atypical opiate drugs. MATERIALS AND METHODS: Head-twitch response was induced in mice by administration of either 5-hydroxytryptophan (5-HTP) or the 5-HT2A/C agonist (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI). Dose-effect curves of atypical opiate drugs [(+/-)-tramadol, (-)-methadone and levorphanol], morphine, and other psychoactive drugs (fluvoxamine, desipramine, nefazodone, and clozapine) were performed. Opioid mechanisms were investigated by administration of naloxone. RESULTS: All the opiates tested reduced both 5-HTP and DOI-induced behavior in a naloxone-reversible fashion, atypical opiates being more effective. The effects of the other drugs depended on the protocol, clozapine being the most effective. CONCLUSIONS: Combined 5-HT and opioid properties result in a greater efficacy in antagonizing 5-HT2A-related behavior. These results provide behavioral evidence to support convergent effects of the 5-HT and opioid systems in discrete brain areas, offering the potential for therapeutic advances in the management of refractory stereotypes and compulsive behaviors.

The role of 5-HT1A receptors in research strategy for extensive pain treatment.

In the last few years, there has been a great increase in our understanding of pain mechanisms. Given the complexity of the mechanisms involved in pain modulation, it is surprising that the pharmacological control of pain through the application of relatively simple analgesics can be effective. Nevertheless, the application of single analgesics is not always effective in diverse painful conditions such as chronic pain syndromes. In these circumstances, we can take advantage of the complexity of pain regulation and try to identify new targets in these intricate processes. It is becoming clear that the combination of different mechanisms, which improves efficacy with reduced toxicity, is necessary for the reliable pharmacotherapy of pain, and is at the forefront in the search for better analgesics. Serotonin is involved at multiple levels in the regulation of nociception. In particular, the raphe nuclei may play a crucial role in integrating the nociceptive and affective information through descending projections to the spinal cord and ascending projections to the forebrain. In these nuclei, 5-HT1A receptors function as somatodendritic autoreceptors controlling the release of serotonin in terminal areas. Different studies have shown that, by preventing this inhibitory control of serotonin release, it is possible to enhance the analgesic effect of drugs that increase serotonin levels (i.e. antidepressants, opiates, and non-steroidal anti-inflammatory drugs) by facilitating descending, and also ascending, pathways involved in pain modulation. Therefore, 5-HT1A receptors may be used as a new target in the search for new pharmacological approaches in the augmentation of analgesia.

Influence of chronic treatment with olanzapine, clozapine and scopolamine on performance of a learned 8-arm radial maze task in rats.

Cognitive deficit is a significant symptom in schizophrenic patients. Use of atypical antipsychotics has been demonstrated to improve some cognitive functions in schizophrenics, as well as in patients with dementia. However, side effects like sedation and muscarinic antagonism induced by these drugs have detracted from this improvement. We are interested in determining the behavioural effect of acute and chronic treatments with olanzapine and clozapine, two atypical antipsychotics, in a paradigm of working memory, and the influence on behavioural response of possible motor effects during test performance. Unspecific muscarinic antagonist scopolamine has been used for comparison. Male Wistar rats were trained on the 8-arm radial maze up to an accuracy level in choice of 80%. Distance travelled in the maze was also measured during test performance. Acute olanzapine, clozapine and scopolamine caused significant impairment of correct performance. Rats treated with olanzapine and clozapine presented a decrease in motor activity level at the same time. After the test at acute dosage, rats were chronically treated for 14 days with olanzapine, clozapine or scopolamine and 24 h after the last dose were again tested in the 8-arm radial maze. Under this procedure, chronic treatment with olanzapine, clozapine and scopolamine did not impair correct task performance and did not modify distance travelled. We concluded that the sedative effect masked a possible effect on working memory after acute administration of olanzapine and clozapine, whereas chronic treatment with olanzapine, clozapine and scopolamine did not adversely affect working memory performance. In the case of scopolamine, it suggests that chronic muscarinic antagonism does not induce memory impairment and for atypical antipsychotics, it suggests that chronic treatment induced a tolerance to acute motor effects of these drugs.

Antidepressant-like effect of tramadol and its enantiomers in reserpinized mice: comparative study with desipramine, fluvoxamine, venlafaxine and opiates.

Tramadol is a centrally acting analgesic that demonstrates opioid and monoaminergic properties. Several studies have suggested that tramadol could play a role in mood improvement. Moreover, it has previously been shown that tramadol is effective in the forced swimming test in mice and the learned helplessness model in rats, two behavioural models predictive of antidepressant activity. The aim of the present study was to test tramadol and its enantiomers in the reserpine test in mice, a classical observational test widely used in the screening of antidepressant drugs. This test is a non-behavioural method where only objective parameters such as rectal temperature and palprebral ptosis are considered. Moreover, we compared the effects of tramadol and its enantiomers with those of antidepressants (desipramine, fluvoxamine and venlafaxine) and opiates [morphine (-)-methadone and levorphanol]. Racemic tramadol, (-)-tramadol, desipramine and venlafaxine reversed the reserpine syndrome (rectal temperature and ptosis), whereas(+)-tramadol and fluvoxamine only antagonized the reserpine-induced ptosis, without any effect on temperature. Opiates did not reverse reserpine-induced hypothermia. (-)-Methadone showed slight effects regarding reserpine-induced ptosis, morphine and levorphanol had no effect. These results show that tramadol has an effect comparable to clinically effective antidepressants in a test predictive of antidepressant activity, without behavioural implications. Together with other clinical and experimental data, this suggests that tramadol has an inherent antidepressant-like (mood improving) activity, and that this effect could have clinical repercussions on the affective component of pain.

The role of 5-HT1A/B autoreceptors in the antinociceptive effect of systemic administration of acetaminophen.

BACKGROUND: It has been proposed that serotonin participates in the central antinociceptive effect of acetaminophen. The serotonin activity in the brainstem is primarily under the control of 5-HT1A somatodendritic receptors, although some data also suggest the involvement of 5-HT1B receptors. In the presence of serotonin, the blockade of 5-HT(1A/B) receptors at the level of the raphe nuclei leads to an increase in serotonin release in terminal areas, thus improving serotonin functions. This study examines the involvement of 5-HT(1A/B) receptors in the antinociceptive effect of acetaminophen in mice. METHODS: The effects of acetaminophen (600 mg/kg intraperitoneal) followed by different doses of antagonists (WAY 100635 [0.2-0.8 mg/kg subcutaneous] and SB 216641 [0.2-0.8 mg/kg subcutaneous]) or agonists (8-OH-DPAT [0.25-1 mg/kg subcutaneous] and CP 93129 [0.125-0.5 mg/kg subcutaneous]) of 5-HT1A and 5-HT1B receptors, respectively, were determined in the hot-plate test in mice. RESULTS: Acetaminophen (300-800 mg/kg) showed a dose-dependent antinociceptive effect in the hot-plate test in mice. WAY 100635 (0.2-0.8 mg/kg; 5-HT1A antagonist) induced an increase in the antinociceptive effect of 600 mg/kg acetaminophen, but this increase was not dose related. Conversely, 8-OH-DPAT (0.25-1 mg/kg; 5-HT1A agonist) decreased the antinociceptive effect of acetaminophen. SB 216641 (0.2-0.8 mg/kg; 5-HT1B antagonist) induced a dose-related increase in the antinociceptive effect of acetaminophen, and CP 93129 (0.25 mg/kg; 5-HT1B agonist) significantly decreased the antinociceptive effect of acetaminophen. CONCLUSIONS: These results suggest that the combination of acetaminophen with compounds having 5-HT1A and 5-HT1B antagonist properties could be a new strategy to improve the analgesia of acetaminophen, thanks to its mild serotonergic properties.

Protective effect of prior acute immune challenge, but not footshock, on inflammation in the rat.

Previous studies have revealed that a single exposure to an acute stress or acute immune stimulus can produce long-lasting changes in the activity and responsiveness of the hypothalamo-pituitary-adrenal (HPA) axis. The HPA axis is believed to be an important component in determining the susceptibility and severity of inflammation in autoimmune disease models such as adjuvant-induced arthritis (AA). In the present study we have tested the hypothesis that a single exposure to either footshock or lipopolysaccharide (LPS) 3 weeks prior to adjuvant injection can alter susceptibility to AA. Changes in HPA axis parameters were also determined. The results demonstrated that prior exposure to LPS conferred resistance to inflammation in AA, which was not related to a delay in onset of inflammation but rather an alteration in susceptibility. In contrast, prior exposure to the acute stress of footshock did not alter susceptibility. HPA axis parameters were increased in adjuvant-injected rats whether inflammation was present or not. These data suggest that prior exposure to acute immune stimuli, but not to acute footshock stress, may alter susceptibility to inflammation in the rat AA model. These changes in susceptibility do not appear to be solely mediated by increases in HPA axis activity, which were apparent in all AA groups irrespective of the presence of inflammation.

Efectividad y seguridad de risperidona a largo plazo en pacientes diagnosticados de esquizofrenia / The efficacy and safety of long-term treatment with risperidone in patients diagnosed from schizophrenia

FUNDAMENTOS: Tras la introducción de los antipsicóticos atípicos y, contrastada su eficacia y efectividad a corto y medio plazo1-8, es necesario realizar un seguimiento de los pacientes esquizofrénicos tratados con estos fármacos para evaluar la efectividad y seguridad de estos fármacos en períodos más prolongados. PACIENTES Y MÉTODOS: Para determinar la incidencia e intensidad con que aparecen los efectos no deseados y estudiar la efectividad del fármaco a largo plazo, se diseñó un estudio abierto, prospectivo, de farmacovigilancia con risperidona, de 18 meses de duración en el que se incluyó a un total de 418 pacientes esquizofrénicos (criterios CIE-10). La evaluación de los pacientes se realizó mediante la escala ICG (Impresión Clínica Global) de gravedad de la enfermedad, la escala Breve de Valoración Psiquiátrica (BPRS) y la escala reducida para la valoración de la discapacidad (DASSV). La evaluación de la seguridad del tratamiento se realizó mediante el registro espontáneo de las reacciones adversas surgidas durante el período de estudio y la subescala UKU para efectos adversos de tipo neurológico. Además, se realizó un estudio sobre la evolución de las dosis de risperidona utilizadas y la influencia de éstas sobre los parámetros del estudio. RESULTADOS: Durante los 18 meses de seguimiento de los pacientes, se observó una mejoría continua, reflejada en las puntuaciones de las escalas de evaluación psicopatológica (BPRS y CGI) y de discapacidad de los pacientes (DAS-SV). Asimismo, se observó una mejoría de las puntuaciones en la subescala de síntomas extrapiramidales de la escala UKU.CONCLUSIONES: La risperidona fue efectiva y se toleró bien en el tratamiento a largo plazo de pacientes esquizofrénicos (AU)

Pindolol, a beta-adrenoceptor blocker/5-hydroxytryptamine(1A/1B) antagonist, enhances the analgesic effect of tramadol.

The ability of pindolol, a beta-adrenoceptor blocker/5-hydroxytryptamine(1A/1B) antagonist, to enhance the clinical antidepressant response to selective serotonin re-uptake inhibitors is generally attributed to a blocking of the feedback that inhibits the serotoninergic neuronal activity mediated by somatodendritic 5-hydroxytryptamine (5-HT)(1A) autoreceptors. The current study examined the ability of pindolol to enhance the analgesic effect of tramadol, an atypical centrally-acting analgesic agent with relatively weak opioid receptor affinity and which, like some antidepressants, is able to inhibit the re-uptake of 5-HT in the raphe nuclei. Racemic pindolol (2 mg/kg, s.c.), rendered analgesic a non-effective acute dose of tramadol (10-40 mg/kg, i.p.) in two nociceptive tests: a hot plate test in mice and a plantar test in rats. Moreover, (+/-)8-OH-DPAT (0.125-1 mg/kg, s.c.), a selective 5-HT(1A) agonist, reduces the analgesic effect of tramadol in the same tests. These results suggest an implication of the somatodendritic 5-HT(1A) receptors in the analgesic effect of tramadol and open a new adjuvant analgesic strategy for the use of this compound.