Mujeeb U. Shad

Hippocampal Changes Associated with Early-Life Adversity and Vulnerability to Depression

BACKGROUND Smaller hippocampal volume has been reported in some adult and pediatric studies of unipolar major depressive disorder. It is not clear whether the smaller hippocampal volume precedes or is a consequence of the illness. Early-life adversity is associated with both smaller hippocampal volume and increased vulnerability to depressive disorder. Hippocampal changes may mediate the relationship between early-life adversity and depressive illness in a subset of patients. However, there are no reports of longitudinal clinical studies that have examined this issue. METHODS Thirty adolescents with unipolar major depressive disorder, 22 adolescent volunteers with no personal history of a psychiatric illness including depression but who were at high risk for developing depression by virtue of parental depression (high-risk group), and 35 adolescent volunteers with no personal or family history of a psychiatric disorder (control subjects) underwent volumetric magnetic resonance imaging studies. Information was also gathered on early and recent adverse experiences with standard interviews. The participants were followed for up to 5 years to assess the onset and clinical course of depression. RESULTS Depressed and high-risk groups had significantly smaller left and right hippocampal volumes than control subjects. Higher levels of early-life adversity were associated with smaller hippocampal volumes. Smaller hippocampal volume partially mediated the effect of early-life adversity on depression during longitudinal follow-up. CONCLUSIONS Smaller hippocampal volume in adolescents at high risk for depression suggests that it may be a vulnerability marker for the illness. Early-life adversity may interact with genetic vulnerability to induce hippocampal changes, potentially increasing the risk for depressive disorder.

Insight and prefrontal cortex in first-episode Schizophrenia

Few studies have investigated the neurobiological basis of impaired insight in antipsychotic-naive schizophrenia. However, the relationship between insight and specific prefrontally mediated cognitive functions suggests that insight deficits may be an expression of prefrontal cortical dysfunction. This study was designed to examine the relationship among insight, neurocognition, and dorsolateral prefrontal cortex (DLPFC) volumes in first-episode antipsychotic-naive schizophrenia subjects. DLPFC volumes were compared between 35 first-episode schizophrenia subjects with good (n = 17) and poor insight (n = 18). Morphometric measurements were based on MRI scans by trained raters blind to clinical information. First-episode schizophrenia subjects with poor insight showed decreased right DLPFC volumes relative to those with good insight. In addition, those with poor insight had higher levels of perseverative errors (PEs) on the Wisconsin Card Sort Test (WCST). No differences in other neuropsychological measures were found between the good and poor insight groups. Similarly, no differences were found between schizophrenia subjects with good versus poor insight on any of the psychopathological measures employed in this study. These findings suggest that poor insight in schizophrenia may be a function of specific prefrontally mediated neurocognitive deficits rather than a global impairment in neuropsychological functioning or different profiles of psychopathology.

Prefrontal subregions and dimensions of insight in first-episode schizophrenia — A pilot study

Deficits in insight are multidimensional, and include symptom unawareness and misattribution. We and others have observed that these deficits may be related to a prefrontal dysfunction. However, few studies have examined the relationship between specific prefrontal sub-regions and the awareness and attributional dimensions of insight in schizophrenia. This study examined the correlation between insight dimensions of awareness and attribution of symptoms and dorsolateral prefrontal cortex (DLPFC) and orbitofrontal cortex (OFC) volume in 14 subjects with first-episode, antipsychotic-naïve (FEAN) schizophrenia. In addition, 21 healthy subjects provided control data for volumetric assessments. Insight was assessed with Scale to Assess Unawareness of Mental Disorders. Morphometric assessments were adjusted for intra-cranial volume and were conducted by trained raters blind to clinical information using BRAINS-2. Average scores on current awareness of symptoms (1=aware; 5=unaware) were negatively correlated with right DLPFC volume and average scores on current attribution of symptoms (1=attribute; 5=misattribute) with right medial OFC volume. Unawareness and misattribution of symptoms in FEAN schizophrenia may have distinct neuroanatomical bases. DLPFC deficits may have resulted in illness unawareness by interfering with self-monitoring, while OFC abnormalities may have mediated symptom misattribution by conferring aberrant salience to perceived symptomatology.

Neurobiological underpinnings of insight deficits in schizophrenia

Impaired insight into illness is commonly observed across various psychiatric illnesses, but is most frequent in patients with schizophrenia. The clinical relevance and public health impact of poor insight is reflected by its close association with important clinical outcome measures, such as treatment non-adherence, lower psychosocial functioning, poor prognosis, involuntary hospitalization, and higher utilization of emergency services. Although the neurobiology of insight has not been determined, data from neurocognitive and a few structural imaging studies provide some understanding of the neurobiological underpinnings of insight function in schizophrenia. Using published and preliminary data, we propose a hypothetical model of insight that may help initiate neurobiological investigations in this complex area.

Gray matter differences between healthy and depressed adolescents: a voxel-based morphometry study.

BACKGROUND Major depressive disorder (MDD) frequently begins during adolescence and is associated with significant morbidity and mortality. However, little is known about the neurobiology of adolescent depression. A better understanding of the neurobiology will be helpful in developing more effective preventive and treatment interventions for this highly disabling illness. METHODS Using a voxel-based morphometric method, the study compared gray matter and white matter volumes in 22 adolescents with MDD and 22 age- and gender-matched normal controls. RESULTS Compared with controls, depressed adolescents had smaller gray matter volume in the frontal lobe and caudate nucleus bilaterally and right superior and middle temporal gyri. However, the groups did not differ significantly on white matter volume. CONCLUSIONS These findings in depressed adolescents are consistent with the previous findings of gray matter abnormalities in frontolimbic areas and the striatum in depressed adults and suggest the presence of these structural changes at the onset of depressive illness.

Neurobiology of self-awareness in schizophrenia: An fMRI study

Self-awareness (SA) is one of the core domains of higher cortical functions and is frequently compromised in schizophrenia. Deficits in SA have been associated with functional and psychosocial impairment in this patient population. However, despite its clinical significance, only a few studies have examined the neural substrates of self-referential processing in schizophrenia. The aim of this study was to assess self-awareness in schizophrenia using a functional magnetic resonance imaging (fMRI) paradigm designed to elicit judgments of self-reference in a simulated social context. While scanned, volunteers looked at visually-displayed sentences that had the volunteers own first name (self-directed sentence-stimulus) or an unknown other persons first name (other-directed sentence stimulus) as the grammatical subject of the sentence. The volunteers were asked to discern whether each sentence-stimulus was about the volunteer personally (during a self-referential cue epoch) or asked whether each statement was about someone else (during an other-referential cue epoch). We predicted that individuals with schizophrenia would demonstrate altered functional activation to self- and other-directed sentence-stimuli as compared to controls. Fifteen controls and seventeen schizophrenia volunteers completed clinical assessments and SA fMRI task on a 3T Philips 3.0 T Achieva system. The results showed significantly greater activation in schizophrenia compared to controls for cortical midline structures in response to self- vs. other-directed sentence-stimuli. These findings support results from earlier studies and demonstrate selective alteration in the activation of cortical midline structures associated with evaluations of self-reference in schizophrenia as compared to controls.

Efficacy and tolerability of olanzapine in the treatment of schizotypal personality disorder

BACKGROUND Few treatment studies of schizotypal personality disorder (SPD) have investigated the new, atypical antipsychotic drugs. This study examined the efficacy and tolerability of olanzapine, an atypical antipsychotic drug, in a series of patients with DSM-IV diagnosed schizotypal personality disorder. METHOD This was a 26-week, open-label study with flexible dose design in 11 subjects with a diagnosis of schizotypal personality disorder based on Structured Clinical Interview for DSM-IV (SCID) and Personality Disorder Examination (PDE Journal of Psychiatric Disorders 1 (1987) 1). Subjects were treated with a low dose (average 9.32 mg/day) of olanzapine. Psychopathology was assessed at baseline and at the end of the study and analyzed with last observation carried forward analysis. RESULTS Patients showed significant improvements in psychosis and depression ratings, as well as in overall functioning. Olanzapine was well tolerated, though significant weight gain was observed. CONCLUSION This study provides preliminary data regarding olanzapine efficacy and tolerability in schizotypal personality disorder subjects. These data need to be confirmed in larger controlled clinical trials.

Novel combination strategy to optimize treatment for PTSD

Post‐traumatic stress disorder (PTSD) is increasingly recognized as a serious and potentially debilitating condition in combat veterans returning from Iraq and Afghanistan. Exposure to a potentially life‐threatening event such as military combat may be followed by PTSD. Despite recent advances in pharmacotherapy for PTSD, monotherapy with the currently available medications is only partially effective, as demonstrated in large clinical trials of combat veterans with PTSD. This underscores the need to investigate novel combination strategies to enhance treatment response in PTSD. The α‐1 adrenergic receptor (AR) antagonist, prazosin, appears promising in recent studies for its capacity to reduce trauma‐related nightmares (a group B night‐time intrusion symptom) and insomnia (a group D night‐time arousal symptom), while recent evidence supports using the β‐AR antagonist, propranolol, to dampen the emotional content of traumatic memories (daytime intrusion symptoms including flashbacks, intrusive recollections of traumatic event, and heightened physiological reactivity/responsivity to trauma reminders). In this review, we present data supporting the potential utility of combined drug regimen (prazosin and propranolol) acting through different noradrenergic mechanisms, with the potential to target more than one set of PTSD symptoms to optimize PTSD treatment. Copyright

Neurobiology of Decision Making in Depressed Adolescents: A Functional Magnetic Resonance Imaging Study

OBJECTIVE Despite evidence that impaired reward- and risk-related behavior during adolescence can have potentially serious short- and long-term consequences, few studies have investigated the impact of depression on reward-related selection in adolescents. This study examined the relationship between reward-related behavior and prefrontal activations in depressed and healthy adolescents during a decision-making task. METHOD A total of 22 adolescents with no personal or family history of psychiatric illness and 22 adolescents with major depressive disorder were administered a monetary, two-option decision-making task, the Wheel of Fortune, using a functional magnetic resonance imaging protocol. The analysis was focused on the selection phase, i.e., the first phase of the decision-making process, which typically includes two more phases, the anticipation of outcome and the feedback. RESULTS Similar prefrontal regions were activated in healthy and depressed adolescents during reward-related selection. However, in a contrast involving the selection of high-risk (low-probability/high-magnitude reward) versus equal-risk (50% chance of reward) options, healthy adolescents showed greater activation than patients in the right lateral orbitofrontal cortex (OFC), whereas participants with depression showed greater activation than healthy subjects in the left dorsal OFC and right caudal anterior cingulate cortex. In addition, healthy adolescents, but not participants with depression, showed a negative correlation between high-risk behavior and neuronal activation in prespecified prefrontal regions. CONCLUSIONS These results suggest subtle changes in the neural responses to reward selection in depressed adolescents. These findings should be replicated in larger samples, and the association of these neuronal changes with treatment response and prognosis should be examined.

Attenuation of the Effects of Corticosteroids on Declarative Memory with Lamotrigine

An extensive animal literature suggests that excessive corticosteroid exposure is associated with changes in memory and the hippocampus. Agents that decrease glutamate attenuate corticosteroid effects on the hippocampus. Minimal data are available on preventing or reversing corticosteroid effects on the human hippocampus. We previously reported that open-label lamotrigine was associated with significant improvement in declarative memory in corticosteroid-treated patients. We now examine the impact of 24 weeks of randomized, placebo-controlled lamotrigine therapy on declarative memory (primary aim) and hippocampal volume (secondary aim) in 28 patients (n=16 for lamotrigine, n=12 for placebo) taking prescription corticosteroids. All participants with data from at least one postbaseline assessment (n=9 for lamotrigine, n=11 for placebo) were included in the analysis. Declarative memory was assessed with the Rey Auditory Verbal Learning Test (RAVLT) at baseline and weeks 12 and 24. Hippocampal and total brain volumes were manually traced from MRI scans obtained at baseline and week 24. On the basis of an ANCOVA analysis, total words learned on the RAVLT at exit were significantly greater in the lamotrigine group (n=8, missing data or dropouts n=8) compared to the placebo group (n=11, dropout n=1). RAVLT scores in the lamotrigine group increased from mildly impaired to average range. Hippocampal volume changes were small in both lamotrigine (n=7) and placebo (n=7) groups during the 24-week assessment period and between-group differences were not significant. Results suggest that lamotrigine may improve declarative memory in patients taking prescription corticosteroids although differential dropout rate in the two groups is a concern.