Ricardo Cáceda

Neurotensin: role in psychiatric and neurological diseases.

Neurotensin (NT), an endogenous brain-gut peptide, has a close anatomical and functional relationship with the mesocorticolimbic and neostriatal dopamine system. Dysregulation of NT neurotransmission in this system has been hypothesized to be involved in the pathogenesis of schizophrenia. Additionally, NT containing circuits have been demonstrated to mediate some of the mechanisms of action of antipsychotic drugs, as well as the rewarding and/or sensitizing properties of drugs of abuse. NT receptors have been suggested to be novel targets for the treatment of psychoses or drug addiction.

Impulsive choice and psychological pain in acutely suicidal depressed patients

Objective Despite identification of several risk factors, suicide prediction and prevention is still a clinical challenge. Suicide can be seen as a consequence of poor decision making triggered by overwhelming psychological pain. We examined the relationship of choice impulsivity and psychological pain in depressed patients with acute suicidality. Methods Impulsive choice (delay discounting), psychological pain, and clinical characteristics were assessed in four groups of adults (N = 20–22): a) depressed patients within 72 hours after a suicide attempt, b) depressed patients with active suicidal ideation, c) nonsuicidal depressed patients, and d) healthy controls. Results Impulsive choice was higher in the suicide attempt (0.114 [0.027]) and ideation (0.099 [0.020]) groups compared with nonsuicidal depressed (0.079 [0.020]) and healthy (0.066 [0.019]) individuals (F(3,79) = 3.06, p = .042). Psychological pain data showed a similar profile (F(3,78) = 43.48, p < .001), with 43.4 (2.9) rating of psychological pain for the suicide attempt, 54.3 (2.2) for suicide ideation, 37.0 (3.2) for nonsuicidal depressed, and 13.7 (0.5) for healthy groups. Within the suicide attempt group, persisting suicidal ideation was associated with more severe depression (36.6 [2.9] versus 21.5 [3.1], p = .007) and choice impulsivity (0.134 [0.03] versus 0.078 [0.04], p = .015). Both measures normalized within a week: depression (29.9 [2.6] versus 14.4 [3.0], p = .006) and choice impulsivity (0.114 [0.026] versus 0.066 [0.032], p = .019). Conclusions Transient impulsive choice abnormalities are found in a subset of those who attempt suicide. Both, suicidal ideation and behavior were associated with choice impulsivity and intense psychological pain.

Virally Mediated Increased Neurotensin 1 Receptor in the Nucleus Accumbens Decreases Behavioral Effects of Mesolimbic System Activation

Dopamine receptor agonist and NMDA receptor antagonist activation of the mesolimbic dopamine system increases locomotion and disrupts prepulse inhibition of the acoustic startle response (PPI), paradigms frequently used to study both the pharmacology of antipsychotic drugs and drugs of abuse. In rats, virally mediated overexpression of the neurotensin 1 (NT1) receptor in the nucleus accumbens antagonized d-amphetamine- and dizocilpine-induced PPI disruption, hyperlocomotion, and d-amphetamine-induced rearing. The NT receptor antagonist SR 142948A [2-[[5-(2,6-dimethoxyphenyl)-1-(4-N-(3-dimethylaminopropyl)-N-methylcarbamoyl)-2-isopropylphenyl)-1H-pyrazole-3-carbonyl]amino] adamantane-2-carboxylic acid, hydrochloride] blocked inhibition of dizocilpine-induced hyperlocomotion mediated by overexpression of the NT1 receptor. Together, these results suggest that increased nucleus accumbens NT neurotransmission, via the NT1 receptor, can decrease the effects of activation of the mesolimbic dopamine system and disruption of the glutamatergic input from limbic cortices, resembling the action of the atypical antipsychotic drug clozapine. In contrast to clozapine, virally mediated overexpression of the NT1 receptor in the nucleus accumbens had prolonged protective effects (up to 4 weeks after viral injection) without perturbing baseline PPI and locomotor behaviors. These data further confirm the NT1 receptor as the receptor mediating the antistimulant- and antipsychotic-like properties of NT and provide rationale for the development of NT1 receptor agonists as novel antipsychotic drugs. In addition, the NT1 receptor vector might be a valuable tool for understanding the mechanism of action of antipsychotic drugs and drugs of abuse and may have potential therapeutic applications.

Mode of effective connectivity within a putative neural network differentiates moral cognitions related to care and justice ethics.

Background Moral sensitivity refers to the interpretive awareness of moral conflict and can be justice or care oriented. Justice ethics is associated primarily with human rights and the application of moral rules, whereas care ethics is related to human needs and a situational approach involving social emotions. Among the core brain regions involved in moral issue processing are: medial prefrontal cortex, anterior (ACC) and posterior (PCC) cingulate cortex, posterior superior temporal sulcus (pSTS), insula and amygdala. This study sought to inform the long standing debate of whether care and justice moral ethics represent one or two different forms of cognition. Methodology/Principal Findings Model-free and model-based connectivity analysis were used to identify functional neural networks underlying care and justice ethics for a moral sensitivity task. In addition to modest differences in patterns of associated neural activity, distinct modes of functional and effective connectivity were observed for moral sensitivity for care and justice issues that were modulated by individual variation in moral ability. Conclusions/Significance These results support a neurobiological differentiation between care and justice ethics and suggest that human moral behavior reflects the outcome of integrating opposing rule-based, self-other perspectives, and emotional responses.

Involvement of Neuropeptide Systems in Schizophrenia: Human Studies

Neuropeptides are heterogeneously distributed throughout the digestive, circulatory, and nervous systems and serve as neurotransmitters, neuromodulators, and hormones. Neuropeptides are phylogenetically conserved and have been demonstrated to regulate numerous behaviors. They have been hypothesized to be pathologically involved in several psychiatric disorders, including schizophrenia. On the basis of preclinical data, numerous studies have sought to examine the role of neuropeptide systems in schizophrenia. This chapter reviews the clinical data, linking alterations in neuropeptide systems to the etiology, pathophysiology, and treatment of schizophrenia. Data for the following neuropeptide systems are included: arginine-vasopressin, cholecystokinin (CCK), corticotropin-releasing factor (CRF), interleukins, neuregulin 1 (NRG1), neurotensin (NT), neuropeptide Y (NPY), opioids, secretin, somatostatin, tachykinins, thyrotropin-releasing hormone (TRH), and vasoactive intestinal peptide (VIP). Data from cerebrospinal fluid (CSF), postmortem and genetic studies, as well as clinical trials are described. Despite the inherent difficulties associated with human studies (including small sample size, variable duration of illness, medication status, the presence of comorbid psychiatric disorders, and diagnostic heterogeneity), several findings are noteworthy. Postmortem studies support disease-related alterations in several neuropeptide systems in the frontal and temporal cortices. The strongest genetic evidence supporting a role for neuropeptides in schizophrenia are those studies linking polymorphisms in NRG1 and the CCKA receptor with schizophrenia. Finally, the only compounds that act directly on neuropeptide systems that have demonstrated therapeutic efficacy in schizophrenia are neurokinin receptor antagonists. Clearly, additional investigation into the role of neuropeptide systems in the etiology, pathophysiology, and treatment of schizophrenia is warranted.

The role of endogenous neurotensin in psychostimulant-induced disruption of prepulse inhibition and locomotion

The neuropeptide neurotensin (NT) is closely associated with dopaminergic and glutamatergic systems in the rat brain. Central injection of NT into the nucleus accumbens (NAcc) or peripheral administration of NT receptor agonists, reduces many of the behavioral effects of psychostimulants. However, the role of endogenous NT in the behavioral effects of psychostimulants (e.g. DA agonists and NMDA receptor antagonists) remains unclear. Using a NTR antagonist, SR142948A, the current studies were designed to examine the role of endogenous NT in DA receptor agonist- and NMDA receptor antagonist-induced disruption of prepulse inhibition of the acoustic startle response (PPI), locomotor hyperactivity and brain-region specific c-fos mRNA expression. Adult male rats received a single i.p. injection of SR142948A or vehicle followed by D-amphetamine, apomorphine or dizocilpine challenge. SR142948A had no effect on baseline PPI, but dose-dependently attenuated d-amphetamine- and dizocilpine-induced PPI disruption and enhanced apomorphine-induced PPI disruption. SR142948A did not significantly affect either baseline locomotor activity or stimulant-induced hyperlocomotion. Systemic SR142948A administration prevented c-fos mRNA induction in mesolimbic terminal fields (prefrontal cortex, lateral septum, NAcc, ventral subiculum) induced by all three psychostimulants implicating the VTA as the site for NT modulation of stimulant-induced PPI disruption. Further characterization of the NT system may be valuable to find clinical useful compounds for schizophrenia and drug addiction.

Response to unfairness across the suicide risk spectrum

Suicidal behavior is frequently triggered by social crises, such as familial, romantic, social or work-related conflict. A variety of cognitive and social functioning impairments has been associated with suicidal thoughts and acts. One of the precipitating and perpetuating factors of social conflict is the desire for retribution after a perceived offense, even at ones own detriment. We utilized the Ultimatum Game-a behavioral economic task which examines the behavioral response to perceived unfairness-in order to characterize the response to unfairness across the acute suicide risk spectrum. We examined five groups of adult individuals of both genders (n = 204): High- and Low-Lethality recent Suicide Attempters, Suicidal Ideators, Non-Suicidal Depressed Patients; and Healthy Controls. We also measured demographic and clinical variables. Even though all depressed groups showed similar rejection rates in the Ultimatum Game, there was a higher likelihood of rejecting offers in the low stakes condition in all acutely suicidal groups compared with healthy controls. Stake size, offer, education, and gender of the proposer were significantly associated with rejection rates. Acutely suicidal patients may be more vulnerable to adverse interpersonal interactions. Further characterization of social behavior may provide targets for secondary and tertiary prevention for high-risk individuals.

Repetitive transcranial magnetic stimulation for apathy in mild cognitive impairment: A double-blind, randomized, sham-controlled, cross-over pilot study

Apathy is a common and disabling behavioral concomitant of many neurodegenerative conditions. The presence of apathy with Mild Cognitive Impairment (MCI) is linked with heightened rates of conversion to Alzheimers disease. Improving apathy may slow the neurodegenerative process. The objective was to establish the efficacy of repetitive transcranial magnetic stimulation (rTMS) in improving apathy in older adults with MCI. An 8-week, double-blind, randomized, sham-controlled cross-over study was conducted in nine subjects (66 ± 9 years) with apathy and MCI. Subjects were randomized to rTMS or sham treatment (5 days/week) for 2 weeks following which they underwent a 4-week treatment-free period. Subjects then crossed-over to receive the other treatment for 2 weeks. The primary (apathy (AES-C)) and secondary (cognition (3MS & MMSE), executive function (TMT-A & TMT-B), and clinical global impression (CGI)) outcomes were assessed at baseline, 2, 6, and 8 weeks. After adjusting for baseline, there was a significantly greater improvement in the AES-C with rTMS compared to sham treatment at 2 weeks. There was significantly greater improvement in 3MS, MMSE, TMT-A, and CGI-I with rTMS compared to the sham treatment. This study establishes that rTMS is efficacious in improving apathy in subjects with MCI.

A probe in the connection between inflammation, cognition and suicide:

Background: Increased inflammation is linked to suicide risk. However, it is unclear whether increased inflammation drives suicidal crises or is a trait associated with lifetime suicidal behavior. Limited data exist on the sources of increased inflammation observed in suicidal patients and on its downstream effects. Aims: To examine factors associated with inflammation and with suicidal ideation severity in acutely suicidal depressed patients. Methods: Fifty-two adult depressed patients of both sexes hospitalized for severe suicidal ideation were characterized for suicidality, depression, anxiety, medical comorbidity, psychological and physical pain, impulsivity, verbal fluency, C-reactive protein (CRP) and interleukin (IL) 6. Two generalized linear models were performed with either CRP or suicidal ideation severity as dependent variables. Results: CRP levels were positively associated with age, body mass index (BMI), IL6, current physical pain and number of lifetime suicide attempts. Suicidal ideation severity was not significantly correlated with either CRP or IL6. Suicidal ideation severity was positively associated with female sex, presence of an anxiety disorder, current physical pain, number of lifetime suicide attempts and with delay discounting for medium and large losses. Conclusions: Increased inflammation is not associated with acute suicidal risk, but seems to represent a trait associated with lifetime suicidal behavior.

Exploration of the Association Between Physical Health and Suicidal Behavior in Psychiatric Outpatients in Rural America

Objective Evidence reveals a link between poor physical health and suicide. The physical health of rural, adult psychiatric outpatients with a history of suicide was examined. Methods The medical records of 192 patients seen at a tertiary-level academic medical center were examined for demographics, psychiatric and medical history, and self-reported measures of depression, anxiety, childhood trauma, and health status. Results The 48 subjects who endorsed a history of suicide attempts evidenced more medical conditions than those who had not made a suicide attempt (t = 2.91, P = 0.005). Conclusions The results support the hypothesis of increased health risks in patients with a history of suicide attempts and highlight the need for targeted health interventions.