Hippocampal neuroplasticity in major depressive disorder.

One of the most replicated findings has been that hippocampus volume is decreased in patients with major depressive disorder (MDD). Recent volumetric magnetic resonance imaging (MRI) studies suggest that localized differences in hippocampal volume may be more prominent than global differences. Preclinical and post-mortem studies in MDD indicated that different subfields of the hippocampus may respond differently to stress and may also have differential levels of plasticity in response to antidepressant treatment. Advances in high-field MRI allowed researchers to visualize and measure hippocampal subfield volumes in MDD patients in vivo. The results of these studies provide the first in vivo evidence that hippocampal volume reductions in MDD are specific to the cornu ammonis and dentate gyrus hippocampal subfields, findings that appear, on the surface, consistent with preclinical evidence for localized mechanisms of hippocampal neuroplasticity. In this review we discuss how recent advances in neuroimaging allow researchers to further understand hippocampal neuroplasticity in MDD and how it is related to antidepressant treatment, memory function, and disease progression.

Cognitive distortions in an acutely traumatized sample: an investigation of predictive power and neural correlates.

BACKGROUND: Current theories of post-traumatic stress disorder (PTSD) place considerable emphasis on the role cognitive distortions such as self-blame, hopelessness or preoccupation with danger play in the etiology and maintenance of the disorder. Previous studies have shown that cognitive distortions in the early aftermath of traumatic events can predict future PTSD severity but, to date, no studies have investigated the neural correlates of this association. METHOD: We conducted a prospective study with 106 acutely traumatized subjects, assessing symptom severity at three time points within the first 3 months post-trauma. A subsample of 20 subjects additionally underwent a functional 4-T magnetic resonance imaging (MRI) scan at 2 to 4 months post-trauma. RESULTS: Cognitive distortions proved to be a significant predictor of concurrent symptom severity in addition to diagnostic status, but did not predict future symptom severity or diagnostic status over and above the initial symptom severity. Cognitive distortions were correlated with blood oxygen level-dependent (BOLD) signal strength in brain regions previously implicated in visual processing, imagery and autobiographic memory recall. Intrusion characteristics accounted for most of these correlations. CONCLUSIONS: This investigation revealed significant predictive value of cognitive distortions concerning concurrent PTSD severity and also established a significant relationship between cognitive distortions and neural activations during trauma recall in an acutely traumatized sample. These data indicate a direct link between the extent of cognitive distortions and the intrusive nature of trauma memories.

Default mode network connectivity as a predictor of post-traumatic stress disorder symptom severity in acutely traumatized subjects.

OBJECTIVE: The goal of this study was to investigate the relationship between default mode network connectivity and the severity of post-traumatic stress disorder (PTSD) symptoms in a sample of eleven acutely traumatized subjects. METHOD: Participants underwent a 5.5 min resting functional magnetic resonance imaging scan. Brain areas whose activity positively correlated with that of the posterior cingulate/precuneus (PCC) were assessed. To assess the relationship between severity of PTSD symptoms and PCC connectivity, the contrast image representing areas positively correlated with the PCC was correlated with the subjects' Clinician Administered PTSD Scale scores. RESULTS: Results suggest that resting state connectivity of the PCC with the perigenual anterior cingulate and the right amygdala is associated with current PTSD symptoms and that correlation with the right amygdala predicts future PTSD symptoms. CONCLUSION: These results may contribute to the development of prognostic tools to distinguish between those who will and those who will not develop PTSD.

In vivo quantification of hippocampal subfields using 4.7 T fast spin echo imaging.

Several neuropsychiatric disorders involving hippocampal structural changes have been studied extensively using volumetric magnetic resonance imaging (MRI). These studies have mostly measured total hippocampal volume while the present study aimed to delineate and measure hippocampal subfields within the whole hippocampus and subdivisions along its longitudinal axis. Images were acquired at 4.7 T in 11 healthy subjects (5 males and 6 females, aged 23-56 years), using a fast spin echo (FSE) sequence with 0.52 x 0.68 x 1.0 mm(3) native resolution, collecting 90 contiguous coronal slices. Subiculum, cornu ammonis (CA1-3), and dentate gyrus were traced manually within the hippocampal head, body, and tail. We reported volumes for the subfields and demonstrated differences in the distribution within the hippocampus and its parts. The biggest part of the dentate gyrus was located in the hippocampal body, following the hippocampal head and tail. In contrast, the hippocampal head had the largest part of CA1-3, following the hippocampal body and tail. The hippocampal tail had the smallest portion of the subiculum compared to hippocampal head and tail. Subfield volumes were consistent between hemispheres and showed distributions within the longitudinal subdivisions that were consistent with histological data. Direct measurements of subfield distribution along the longitudinal axis of the hippocampus may be more sensitive to detecting disease effects than total volume measures and the differential distribution of subfield volumes may aid in the interpretation of measurements obtained at lower field strength and spatial resolution.

The role of beta-endorphin in the pathophysiology of major depression.

A role for beta-endorphin (beta-END) in the pathophysiology of major depressive disorder (MDD) is suggested by both animal research and studies examining clinical populations. The major etiological theories of depression include brain regions and neural systems that interact with opioid systems and beta-END. Recent preclinical data have demonstrated multiple roles for beta-END in the regulation of complex homeostatic and behavioural processes that are affected during a depressive episode. Additionally, beta-END inputs to regulatory pathways involving feeding behaviours, motivation, and specific types of motor activity have important implications in defining the biological foundations for specific depressive symptoms. Early research linking beta-END to MDD did so in the context of the hypothalamic-pituitary-adrenal (HPA) axis activity, where it was suggested that HPA axis dysregulation may account for depressive symptoms in some individuals. The primary aims of this paper are to use both preclinical and clinical research (a) to critically review data that explores potential roles for beta-END in the pathophysiology of MDD and (b) to highlight gaps in the literature that limit further development of etiological theories of depression and testable hypotheses. In addition to examining methodological and theoretical challenges of past clinical studies, we summarize studies that have investigated basal beta-END levels in MDD and that have used challenge tests to examine beta-END responses to a variety of experimental paradigms. A brief description of the synthesis, location in the CNS and behavioural pharmacology of this neuropeptide is also provided to frame this discussion. Given the lack of clinical improvement observed with currently available antidepressants in a significant proportion of depressed individuals, it is imperative that novel mechanisms be investigated for antidepressant potential. We conclude that the renewed interest in elucidating the role of beta-END in the pathophysiology of MDD must be paralleled by consensus building within the research community around the heterogeneity inherent in mood disorders, standardization of experimental protocols, improved discrimination of POMC products in analytical techniques and consistent attention paid to important confounds like age and gender.

Posttraumatic stress disorder Part III: health effects of interpersonal violence among women.

TOPIC: The aim of this three-part series is to examine the sufficiency of the posttraumatic stress (PTSD) diagnostic construct to capture the full spectrum of human responses to psychological trauma. Part I (Lasiuk & Hegadoren, 2006a) reviewed the conceptual history of PTSD from the nineteenth century to its inclusion in the third edition of the Diagnostic and Statistical Manual of Mental Disorders (American Psychiatric Association, 1980), while Part II (Lasiuk & Hegadoren, 2006b) described subsequent refinements to the original PTSD diagnostic criteria and highlighted subsequent controversies. PURPOSE: This paper focuses on interpersonal violence (sexual, physical, and emotional abuse/assault) and its sequelae in women. We argue in support of Judith Herman's (1992) conceptualization of the human trauma response as a spectrum, anchored at one end by an acute stress reaction that resolves on its own without treatment, and on the other by "complex" PTSD, with "classic" or "simple" PTSD somewhere between the two. SOURCES OF INFORMATION: he existing theoretical, clinical and research literatures related to humans responses to trauma. CONCLUSION: The paper concludes with a call for the need to increase a gendered perspective in all aspects of trauma research and clinical service delivery.

Social phobia: etiology, neurobiology, and treatment.

Social phobia is a common and often disabling condition, with an etiology that is not established. There is evidence at several levels for an interplay of biological and psychological processes in social phobia. Genetic studies show that both genetic and environmental factors are important, with evidence pointing to associations with 2 genetic conditions, autism and fragile X syndrome. Behavioral inhibition has emerged as an important precursor to social phobia and possibly to other anxiety disorders. Epidemiologic and clinical studies have suggested that factors within the family environment, such as overprotection, overcontrol, modeling of anxiety, criticism, and in some cases abuse, can play a role in the development of social phobia. During childhood, complex interactions between brain system disturbances that mediate responses to negative social cues and factors in the social setting may lead to the development of a distorted set of internal "blueprints" for social behavior. The impact of severe social anxiety on brain systems that mediate behavioral change may prevent patients from learning better "blueprints." These can be taught through cognitive-behavioral therapies. The effective control of social anxiety with medications enables patients to recover; whether recovery can last after discontinuation of medications may depend on whether a new "blueprint" has been developed and whether stable changes in affected brain systems have occurred. Neuroimaging techniques are at the early stage of identifying abnormalities at the neurotransmitter and systems levels.

A rapid high-pressure liquid chromatographic procedure for determination of flumazenil in plasma.

INTRODUCTION: Flumazenil antagonizes the effects of benzodiazepines at gamma-aminobutyric acid (GABA) type A receptors in the central nervous system. Flumazenil has been reported to provoke panic attacks in patients with panic disorder (PD) but not in healthy controls. A rapid high-pressure liquid chromatographic (HPLC) method was developed for determination of flumazenil in plasma samples from PD patients receiving flumazenil and the results obtained with that assay are reported here. METHODS: Samples from 37 PD subjects receiving 2 mg of flumazenil intravenously were analyzed. Extraction under basic conditions was followed by an HPLC assay with UV detection (250 nm). Lamotrigine was used as intermal standard and a standard curve was constructed for each assay run. Flumazenil concentrations were measured in all the subjects in samples collected at 2 and 4 min after the drug administration and in some subjects, measurements were also done in samples collected at 7.5, 15, 30, 45, and 60 min. RESULTS: The procedure was reproducible and linear (from 2.5 to 1000 ng/ml). At 2 and 4 min after flumazenil administration, the concentrations did not differ significantly between panicking and nonpanicking subjects, indicating that the pharmacokinetics of the drug is not the major determinant of the responses. There was a steep decline in the plasma concentration-time profile during the first 4 min, reflecting an extensive and rapid distribution after which the decline was slower. DISCUSSION: The method described here is rapid, replicable, and convenient for the determination of flumazenil in plasma.

Sleep changes during long-term treatment of depression with fluvoxamine--a home-based study.

RATIONALE: The effects of antidepressants on sleep in depression have been extensively investigated, although to date there have been relatively few studies of newer drug classes such as specific serotonin reuptake inhibitors (SSRIs). All reported studies on SSRIs have been conducted in patients admitted to sleep laboratories and very few longitudinal studies have continued to measure sleep beyond 5 weeks of treatment. The growing trend towards outpatient and community care has highlighted the need for studies of sleep in depression in a more naturalistic setting, and during longer periods of treatment in line with recommended clinical practice. OBJECTIVES: To establish if the changes in sleep architecture and continuity described during early treatment with SSRIs persist after 3 months, to relate these changes to clinical state, and to establish whether home recordings would yield similar results to previous laboratory studies. METHODS: We have recorded objective sleep parameters in 12 depressed patients before and during 12-week treatment with an SSRI, fluvoxamine. All the sleep recordings were performed in the patients' own homes, using the Oxford Medilog system. RESULTS: At 12 weeks, 7/12 patients had responded (HAM-D decreased by > 50%). REM latency showed the expected increase early in treatment; this change was less obvious at weeks 3 and 12. Amount of REM sleep was decreased at day 2 and week 3, but returned to baseline by week 12. Slow wave sleep was slightly increased at day 2 and decreased at week 12. Of the sleep continuity measures, the only significant change was in sleep onset latency, which was increased at week 3; the other measures showed non-significant worsening at night 2 and week 3, but most were better than baseline by 12 weeks. Subjective sleep (the three sleep items on the HAM-D) showed a progressive improvement over time, especially in the responders. CONCLUSIONS: The effects of the SSRI fluvoxamine on objective sleep measures are in the direction predicted by its pharmacological actions and some persist for at least 12 weeks. In addition subjective appraisal of sleep is strongly affected by mood state. All patients found the home recording procedure acceptable and only minimally disruptive.

Response to flumazenil in women with premenstrual dysphoric disorder.

OBJECTIVE: The authors sought to determine whether the administration of flumazenil would induce marked panic symptoms in women suffering from premenstrual dysphoric disorder. METHOD: Ten women with premenstrual dysphoric disorder and 11 comparison subjects were injected with flumazenil or placebo in a double-blind, randomized, balanced crossover design in a single session in the luteal phase of their menstrual cycles. RESULTS: Flumazenil induced a much greater panic response in the women with premenstrual dysphoric disorder than in the comparison subjects. CONCLUSIONS: These preliminary results are consistent with a dysregulation of the g-aminobutyric acid A/benzodiazepine receptor complex during the premenstruum of women suffering from premenstrual dysphoric disorder.

Flumazenil challenge in social phobia.

The benzodiazepine antagonist, flumazenil, can provoke panic attacks in some panic disorder patients. It has been predicted that panic responses to flumazenil may be associated with situational fear. Patients with social phobia frequently experience situational anxiety and panic attacks. The current study tested whether flumazenil induces panic in patients with social phobia. Fourteen patients with social phobia (DSM-III-R) and 14 age- and sex-matched controls were tested in a single session, double blind crossover challenge design, using intravenous flumazenil 2 mg/20 ml or matched placebo infusions 1 hour apart. Panic attacks occurred during flumazenil challenge in 2/14 subjects with social phobia. The rate of panic attacks and the severity of panic symptoms following flumazenil were not significantly greater in patients than in controls. Situational fears that are provoked by social cues therefore do not predict panic responses to flumazenil.

Serotonin reuptake inhibitor withdrawal.

We studied reported withdrawal symptoms in a retrospective chart review of 352 patients treated in an outpatient clinic with the nonselective serotonin reuptake inhibitor clomipramine or with one of the selective serotonin reuptake inhibitors (SSRIs), fluoxetine, fluvoxamine, paroxetine, or sertraline. In 171 patients who were supervised during medication tapering and discontinuation, the most common symptoms were dizziness, lethargy, paresthesia, nausea, vivid dreams, irritability, and lowered mood. When patients with at least one qualitatively new symptom were defined as cases, these symptoms occurred significantly more frequently in patients who had been treated either with one of the shorter half-life SSRIs, fluvoxamine or paroxetine (17.2%), or with clomipramine (30.8%), than in patients taking one of the SSRIs with longer half-life metabolites, sertraline or fluoxetine (1.5%). The rate was not significantly different between the different shorter half-life treatments. Cases treated with fluvoxamine or paroxetine had received a significantly longer period of treatment (median 28 weeks) than noncases (16 weeks), but there were no significant associations with age or with diagnostic grouping. There was a trend toward an association with male sex. The majority of cases occurred despite slowly tapered withdrawal. Symptoms persisted for up to 21 days (mean = 11.8 days) after onset. These symptoms were relieved within 24 hours by restarting the medication, but were not relieved by benzodiazepines or by moclobemide. A role has been suggested for serotonin in coordinating sensory and autonomic function with motor activity. We suggest that this may lead to useful hypotheses about the pathophysiology of withdrawal symptoms from serotonin reuptake inhibitors.

A comparison of the effects of phenelzine treatment with moclobemide treatment on cardiovascular reflexes.

The effects of treatment with phenelzine (n = 15) and moclobemide (n = 20) on heart rate variability and cardiovascular responses to standing were examined using non-invasive beat-to-beat blood pressure (BP) monitoring in an open cross-sectional study. Phenelzine markedly impaired the BP response compared with moclobemide, with 83% vs 15% of patients lacking the normal initial BP overshoot (p < 0.01). BP recovery to supine levels was delayed (median time for diastolic BP 14.5 s after phenelzine vs 4.9 s after moclobemide; p < 0.002). Standing BP at 1 min and its change from supine levels were also significantly lower in the phenelzine group (delta diastolic BP 4 mmHg vs 15 mmHg; p < 0.001). Heart rate responses and variability were preserved and did not differ between treatments. These findings are consistent with impairment of sympathetic function but preservation of parasympathetic responses after phenelzine treatment.