Brain-derived neurotrophic factor and inflammatory markers in school-aged children with early trauma.

OBJECTIVE: The impact of childhood trauma (CT) on brain-derived neurotrophic factor (BDNF) and cytokines levels remains unclear. We investigated the association between CT and changes in BDNF and cytokines plasma levels in children. METHOD: We recruited 36 children with trauma (CT+) and 26 children without trauma (CT-). The presence of CT was based on a clinical interview and by Criteria A of DSM-IV criteria for PTSD. Blood samples were drawn from all children to assess BDNF and cytokines. ancova was performed with psychiatric symptoms and BMI as covariates to evaluate group differences in plasma levels. RESULTS: CT+ showed increased levels of BDNF and TNF-α after excluding children with history of inflammatory disease (P<0.05) when compared with those CT-. IL-12p70, IL-6, IL-8, IL-10, and IL-1ß levels were not statistically different between groups. CONCLUSION: CT+ showed increased BDNF and proinflammatory cytokines levels. The increase in BDNF levels may be an attempt to neutralize the negative effects of CT, while an increase in TNF-a levels be associated with a proinflammatory state after CT. How these changes associated with trauma relate to other biological changes and illness trajectory later in life remain to be further studied.

Staging systems in bipolar disorder: an International Society for Bipolar Disorders Task Force Report.

OBJECTIVE: We discuss the rationale behind staging systems described specifically for bipolar disorders. Current applications, future directions and research gaps in clinical staging models for bipolar disorders are outlined. METHOD: We reviewed the literature pertaining to bipolar disorders, focusing on the first episode onwards. We systematically searched data on staging models for bipolar disorders and allied studies that could inform the concept of staging. RESULTS: We report on several dimensions that are relevant to staging concepts in bipolar disorder. We consider whether staging offers a refinement to current diagnoses by reviewing clinical studies of treatment and functioning and the potential utility of neurocognitive, neuroimaging and peripheral biomarkers. CONCLUSION: Most studies to date indicate that globally defined late-stage patients have a worse overall prognosis and poorer response to standard treatment, consistent with patterns for end-stage medical disorders. We believe it is possible at this juncture to speak broadly of 'early'- and 'late'-stage bipolar disorder. Next steps require further collaborative efforts to consider the details of preillness onset and intermediary stages, and how many additional stages are optimal.

More pernicious course of bipolar disorder in the United States than in many European countries: implications for policy and treatment.

BACKGROUND: There is some controversy but growing evidence that childhood onset bipolar disorder may be more prevalent and run a more difficult course in the United States than some European countries. METHODS: We update and synthesize course of illness data from more than 960 outpatients with bipolar disorder (average age 40) from 4 sites in the U.S. and 3 sites in Netherlands and Germany. After giving informed consent, patients reported on parental history, childhood and lifetime stressors, comorbidities, and illness characteristics. RESULTS: Almost all aspects of bipolar disorder were more adverse in patients from the US compared with Europe, including a significantly higher prevalence of: bipolar disorder in one parent and a mood disorder in both parents; childhood verbal, physical, or sexual abuse; stressors in the year prior to illness onset and the last episode; childhood onsets of bipolar illness; delay to first treatment; anxiety disorder, substance abuse, and medical comorbidity; mood episodes and rapid cycling; and nonresponse to prospective naturalistic treatment. LIMITATIONS: Selection bias in the recruit of patients cannot be ruled out, but convergent data in the literature suggest that this does not account for the findings. Potential mechanisms for the early onset and more adverse course in the U.S. have not been adequately delineated and require further investigation. CONCLUSIONS: The data suggest the need for earlier and more effective long-term treatment intervention in an attempt to ameliorate this adverse course and its associated heavy burden of psychiatric and medical morbidity.

Increased parental history of bipolar disorder in the United States: association with early age of onset.

OBJECTIVE: Early-onset bipolar (BP) disorder and other poor prognosis characteristics are more prevalent in patients from the United States than from the Netherlands and Germany (abbreviated as Europe). We explored the impact of parental loading for affective illness on onset and other characteristics of BP disorder. METHOD: Parental history for unipolar (UP) and bipolar (BP) depression and course of illness characteristics were obtained from self-report in adults (average age 42) with BP disorder. Illness characteristics were examined by χ2 and multinomial logistic regression in relationship to the degree of parental loading: i) both parents negative; ii) one UP disorder; iii) one with BP disorder; and iv) both affected. RESULTS: After controlling for many poor prognosis factors, compared with those from Europe, patients from the United States had more iii) one parent with BP disorder and iv) both parents affected. An early age of onset of BP disorder was independently associated with this increased parental loading for affective disorder. CONCLUSION: Parental history of BP disorder and both parents with a mood disorder were more common in the United States than Europe and were associated with an early onset of bipolar disorder and other poor prognosis characteristics. These findings deserve replication and exploration of the potential mechanisms involved and their therapeutic implications.

Opposite effects of high and low frequency rTMS on mood in depressed patients: relationship to baseline cerebral activity on PET.

BACKGROUND: Optimal parameters of rTMS for antidepressant efficacy in general, or within patients, have not been adequately delineated. METHODS: Using a double-blind, sham-controlled, cross-over design, 22 adult patients with treatment refractory major depression (n=9; bipolar disorder, depressed phase) were randomized to active rTMS (20-Hz or 1-Hz) or sham rTMS conditions and given 5 rTMS treatments per week for two weeks. Repetitive TMS was administered at 100% of motor threshold for 1600 pulses over the left prefrontal cortex using a figure-eight coil. Patients initially randomized to sham rTMS were then exposed to two weeks of active rTMS with each frequency under blinded conditions. Those who received active 20-Hz and 1-Hz rTMS were crossed over to the opposite frequency for two weeks. Improvement in Hamilton Depression ratings were assessed after each two-week treatment phase. PET imaging was used to evaluate the patient's baseline absolute regional cerebral activity (blood flow and metabolism) as potential predictor of clinical response. RESULTS: Changes in depression severity on 1-Hz and 20-Hz rTMS were inversely correlated. PET scans with baseline hypoperfusion (but not hypometabolism) were associated with better improvement on 20-Hz rTMS as predicted. LIMITATIONS: The magnitude of the clinical change with either frequency at 100% motor threshold was not robust, and larger studies with higher intensities of rTMS for longer durations of time should be explored. CONCLUSIONS: High and low frequency rTMS exerts differential effects on depressed mood within individual subjects. The brain activity predictors and correlates of an optimal antidepressant response to rTMS remain to be better defined.

Tranylcypromine vs. lamotrigine in the treatment of refractory bipolar depression: a failed but clinically useful study.

OBJECTIVE: To compare the efficacy and tolerability of tranylcypromine vs. lamotrigine in bipolar depression not responding to conventional antidepressants. METHOD: Bipolar depressed patients received open randomized treatment with tranylcypromine or lamotrigine as add-on to a mood stabilizer during 10 weeks. In a second treatment phase, non-responding patients could receive the opposite drug. Outcome criteria were response (measured with CGI-BP and IDS-C), switch into mania, and completion of the study. RESULTS: Only 20 of 70 planned patients were randomized, due to problems with recruitment, and 19 patients received any medication. During the first treatment phase 5/8 patients (62.5%) responded to tranylcypromine without switch into mania, compared with 4/11 patients (36.4%) on lamotrigine with two switches (statistically not significant). Over both treatment phases, 8/10 patients (80%) receiving tranylcypromine completed the study vs. 5/13 (38.5%) on lamotrigine (likelihood 0.02). CONCLUSION: There still appears to be a role for tranylcypromine in the treatment of refractory bipolar depression. Larger controlled studies are demanded.

The role of psychosocial stress in the onset and progression of bipolar disorder and its comorbidities: the need for earlier and alternative modes of therapeutic intervention.

Psychosocial stress plays an important role at multiple junctures in the onset and course of bipolar disorder. Childhood adversity may be a risk factor for vulnerability to early onset illness, and an array of stressors may be relevant not only to the onset, recurrence, and progression of affective episodes, but the highly prevalent substance abuse comorbidities as well. A substantial group of controlled studies indicate that various cognitive behavioral psychotherapies and psychoeducational approaches may yield better outcomes in bipolar disorder than treatment as usual. Yet these approaches do not appear to be frequently or systematically employed in clinical practice, and this may contribute to the considerable residual morbidity and mortality associated with conventional treatment. Possible practical approaches to reducing this deficit (in an illness that is already underdiagnosed and undertreated even with routine medications) are offered. Without the mobilization of new clinical and public health approaches to earlier and more effective treatment and supportive interventions, bipolar illness will continue to have grave implications for many patients' long-term well being.

Mood switch in bipolar depression: comparison of adjunctive venlafaxine, bupropion and sertraline.

BACKGROUND: Few studies have examined the relative risks of switching into hypomania or mania associated with second-generation antidepressant drugs in bipolar depression. AIMS: To examine the relative acute effects of bupropion, sertraline and venlafaxine as adjuncts to mood stabilisers. METHOD: In a 10-week trial, participants receiving out-patient treatment for bipolar disorder (stratified for rapid cycling) were randomly treated with a flexible dose of one of the antidepressants, or their respective matching placebos, as adjuncts to mood stabilisers. RESULTS: A total of 174 adults with bipolar disorder I, II or not otherwise specified, currently in the depressed phase, were included. All three antidepressants were associated with a similar range of acute response (49-53%) and remission (34-41%). There was a significantly increased risk of switches into hypomania or mania in participants treated with venlafaxine compared with bupropion or sertraline. CONCLUSIONS: More caution appears indicated in the use of venlafaxine rather than bupropion or sertraline in the adjunctive treatment of bipolar depression, especially if there is a prior history of rapid cycling.

Neurobiology of seizures and behavioral abnormalities.

Seizures are both caused by and induce a complex set of neurobiological alterations and adaptations. The animal model of amygdala kindling provides insight into the spatiotemporal evolution of these changes as a function of seizure development and progression. Intracellular, synaptic, and microstructural changes are revealed as related to both the primary pathophysiology of kindled seizure evolution and compensatory secondary, or endogenous anticonvulsant adaptations. At the level of gene expression, the balance of these pathological and adaptive processes (as augmented by exogenous medications) probably determines whether seizures will be manifest or suppressed and could account for aspects of their intermittency. As anxiety and emotion modulation are subserved by many of the same neuroanatomic substrates involved in the evolution of complex partial seizures, particularly those of the medial temporal lobe, it is readily conceptualized how vulnerability to a range of psychiatric disorders could be related to the primary or secondary neurochemical alterations associated with seizure disorders. The discrete and methodologically controlled elucidation of the cascades and spatiotemporal distributions of neurobiological alterations that accompany seizure evolution in the kindling model may help resolve some of the difficulty and complexity of elucidating these biobehavioral relationships in the clinic.

Use of quetiapine in bipolar disorder: a case series with prospective evaluation.

Quetiapine, a new atypical antipsychotic, was added to ongoing treatment of bipolar I outpatients (n=15) for symptoms of illness (mood lability, irritability, psychosis and/or difficulty sleeping). All evaluations were prospectively obtained, with the majority of patients (n=9) showing much or very much improvement on the Clinical Global Impression for Bipolar Disorder (CGI-BP). Somatic complaints were limited. Mean (SD) duration before changes in medication regimens was 134 (100) days. Studies of the use of quetiapine in maintenance treatment of bipolar disorder are warranted.

Lamotrigine reduces spontaneous and evoked GABAA receptor-mediated synaptic transmission in the basolateral amygdala: implications for its effects in seizure and affective disorders.

Lamotrigine (LTG) is an antiepileptic drug that is also effective in the treatment of certain psychiatric disorders. Its anticonvulsant action has been attributed to its ability to block voltage-gated Na(+) channels and reduce glutamate release. LTG also affects GABA-mediated synaptic transmission, but there are conflicting reports as to whether inhibitory transmission is enhanced or suppressed by LTG. We examined the effects of LTG on GABA(A) receptor-mediated synaptic transmission in slices from rat amygdala, a brain area that is particularly important in epileptogenesis and affective disorders. In intracellular recordings, LTG (100 microM) reduced GABA(A) receptor-mediated IPSPs evoked by electrical stimulation in neurons of the basolateral nucleus. In whole-cell recordings, LTG (10, 50 and 100 microM) decreased the frequency and amplitude of spontaneous IPSCs, as well as the amplitude of evoked IPSCs, but had no effect on the kinetics of these currents. LTG also had no effects on the frequency, amplitude or kinetics of miniature IPSCs recorded in the presence of TTX. These results suggest that in the basolateral amygdala, LTG suppresses GABA(A) receptor-mediated synaptic transmission by a direct and/or indirect effect on presynaptic Ca(++) influx. The modulation of inhibitory synaptic transmission may be an important mechanism underlying the psychotropic effects of LTG.

Lack of adverse cognitive effects of 1 Hz and 20 Hz repetitive transcranial magnetic stimulation at 100% of motor threshold over left prefrontal cortex in depression.

OBJECTIVE: The potential therapeutic effects of repetative transcranial magnetic stimulation (rTMS) are being examined in various neuropsychiatric illnesses. This study assesses the cognitive performance of depressed patients receiving high or low frequency rTMS for 10 days. METHODS: 18 depressed patients participated in a randomized double-blind cross-over study exploring the antidepressant effects of 2 weeks (10 daily) of sham, 1 Hz, or 20 Hz rTMS administered over the left dorsolateral prefrontal cortex at 100% of motor threshold (MT). A subgroup completed a battery of cognitive tests at baseline and following each 2-week phase of treatment, and differences in performance were assessed using paired t -tests and were correlated with the degree of clinical improvement using Hamilton Depression Rating Scale scores. RESULTS: There were no major changes in cognitive test scores as a result of 10 days of either 1 Hz or 20 Hz rTMS. Moreover, any minor attenuations in cognition were not related to the degree of clinical improvement. CONCLUSIONS: Cognitive functioning in many domains following 2 weeks of 1 Hz or 20 Hz rTMS at 100% MT over the left dorsolateral prefrontal cortex in depressed patients is not disrupted.

Relationship between prior course of illness and neuroanatomic structures in bipolar disorder: a preliminary study.

OBJECTIVE: In this preliminary study, we examined the relationships between prior course and severity of illness and size of the hippocampus, temporal lobes, and third and lateral ventricles in patients with bipolar disorder. BACKGROUND: The few studies that have investigated relationships between course of illness measures and neuroanatomic structures in patients with bipolar disorder found divergent results. METHOD: Twenty-six outpatients, who met Diagnostic and Statistical Manual, Third Edition - Revised (DSM-III-R) criteria for bipolar disorder, received a magnetic resonance imaging (MRI) scan, from which volumes of the temporal lobes, hippocampi, third ventricle, and areas of the lateral ventricles were calculated. Prior course of illness variables were determined using the NIMH Life-Chart Method and were correlated to the volumetric measures of neuroanatomic structures using multiple regression analyses. RESULTS: A longer duration of illness was paradoxically associated with a larger left temporal lobe volume whether patients with a history of substance abuse were removed from the analyses. CONCLUSIONS: Additional studies are needed to both replicate and further examine the association of prior course of illness and larger hippocampal and ventricular volumes in bipolar disorder.

Post-dexamethasone cortisol correlates with severity of depression before and during carbamazepine treatment in women but not men.

OBJECTIVE: Previous studies show a state-dependent relationship between depression and post-dexamethasone suppression test (DST) cortisol level, as well as differences in DST response with age and gender. METHOD: In this study, 74 research in-patients with affective disorders were given the DST on placebo and in a subgroup following treatment with carbamazepine. Depression was evaluated twice daily with the Bunney-Hamburg (BH) rating scale. Data were examined for the total subject population, by gender and by menopausal status in women. RESULTS: A robust positive correlation was observed between depression severity and post-DST cortisol in pre- and postmenopausal females, but not in males. This relationship persisted in women when restudied on a stable dose of carbamazepine (n=42). CONCLUSION: The pathophysiological implications of this selective positive relationship between severity of depression and post-DST cortisol in women, but not men, should be explored further.

Developmental vulnerabilities to the onset and course of bipolar disorder.

Different types of psychosocial stressors have long been recognized as potential precipitants of both unipolar and bipolar affective episodes and the causative agents in posttraumatic stress disorder (PTSD). New preclinical data have revealed some of the neurobiological mechanisms that could convey the long-term behavioral and biochemical consequences of early stressors. Depending on the timing, quality, quantity, and degree of repetition, maternal deprivation stress in the neonatal rodent can be associated with lifelong anxiety-like behaviors, increases in stress hormones and peptides. and proneness to drug and alcohol administration, in association with acute changes in the rate of neurogenesis and apoptosis (preprogrammed cell death) and decrements in neurotrophic factors and signal transduction enzymes necessary for learning and memory. Patients with bipolar illness who have a history of early extreme adversity (physical or sexual abuse in childhood or adolescence), compared with those without, show an earlier onset of illness, faster cycling frequencies, increased suicidality, more Axis I and Axis II comorbidities (including alcohol and substance abuse), and more time ill in more than 2 years of prospective follow-up. These findings are subject to a variety of interpretations, but to the extent that the more severe course of bipolar illness characteristics are directly and causally related to these early stressful experiences, early recognition and treatment of high-risk children could be crucial in helping to prevent or ameliorate the long-term adverse consequences of these stressors.

Regional cerebral blood flow correlated with flashback intensity in patients with posttraumatic stress disorder.

BACKGROUND: Nuclear imaging studies have examined cerebral blood flow (rCBF) in subjects with posttraumatic stress disorder (PTSD) using symptom evocation paradigms. To date, no such studies have investigated rCBF as related to subjects' reports of flashback intensity. METHODS: Subjects with varying traumatic histories and longstanding PTSD were studied using [15O]-H2O positron emission tomography with an auditory script of their traumatic event. Eight subjects had three resting scans followed by their script and additional scans. Heart rate responses as well as the presence of flashbacks and their intensity were recorded. rCBF was correlated with flashback intensity in each subject's scan. Combined analysis of all subjects' data yielded common regions related to the flashback experience. RESULTS: rCBF correlated directly with flashback intensity in the brainstem, lingula, bilateral insula, right putamen and left hippocampal and perihippocampal, somatosensory and cerebellar regions. Inverse correlations with rCBF were found in bilateral dorsolateral prefrontal, right fusiform and right medial temporal cortices. CONCLUSIONS: This study correlated flashback intensity and rCBF in a group of patients with chronic PTSD suggesting involvement of brainstem, and areas associated with motor control, complex visual/spatial cues and memory.

The Stanley Foundation Bipolar Network. I. Rationale and methods.

BACKGROUND: The Stanley Foundation Bipolar Network (SFBN) was created to address the paucity of help studies in bipolar illness. AIMS: To describe the rationale and methods of the SFBN. METHOD: The SFBN includes five core sites and a number of affiliated sites that have adopted consistent methodology for continuous longitudinal monitoring of patients. Open and controlled studies are performed as patients' symptomatology dictates. RESULTS: The reliability of SFBN raters and the validity of the rating instruments have been established. More than 500 patients are in continuous daily longitudinal follow-up. More than 125 have been randomised to one of three of the newer antidepressants (bupropion, sertraline and venlafaxine) as adjuncts in a study of mood stabilizers and 93 to omega-3 fatty acids. A number of open clinical case series have been published. CONCLUSIONS: Well-characterised patients are followed in a detailed continuous longitudinal fashion in both opportunistic case series and double-blind, randomised controlled trials with reliable and validated measures.

The Stanley Foundation Bipolar Network. 2. Preliminary summary of demographics, course of illness and response to novel treatments.

BACKGROUND: The Stanley Foundation Bipolar Network (SFBN) evaluates treatments, course and clinical and neurobiological markers of response in bipolar illness. AIMS: To give a preliminary summary of emerging findings in these areas. METHOD: Studies with established and potentially antimanic, antidepressant and mood-stabilising agents range from open case series to double-blind randomised clinical trials, and use the same core assessment methodology, thereby optimising the comparability of the outcomes. The National Institute of Mental Health Life Chart Method is the core instrument for retrospective and prospective longitudinal illness description. RESULTS: The first groups of patients enrolled show a considerable degree of past and present symptomatology, psychiatric comorbidity and functional impairment. There are associations of both genetic and early environmental factors with more severe courses of illness. Open case series with add-on olanzapine, lamotrigine, gabapentin or topiramate show a differential spectrum of effectiveness in refractory patients. CONCLUSIONS: The SFBN provides important new data for the understanding and treatment of bipolar disorder.

Input-specific LTP and depotentiation in the basolateral amygdala.

The amygdala plays a central role in emotional memory. The cellular mechanisms by which the amygdala participates in emotional learning are believed to be changes in efficacy of synaptic transmission, similar to long-term potentiation (LTP) and long-term depression (LTD). Although different forms of LTP have been shown in the amygdala, many of their features are still unknown. Here, we use both field potential and intracellular recordings in rat amygdala slices, and show that LTP in the basolateral nucleus, induced by high-frequency stimulation (HFS) of the external capsule is input-specific, can be reversed by low-frequency stimulation (LFS), and can be reinstated by HFS. These synapse-specific, reversible changes in synaptic strength in the basolateral nucleus of the amygdala may be important to amygdala's role in emotional memory.

Axis I psychiatric comorbidity and its relationship to historical illness variables in 288 patients with bipolar disorder.

OBJECTIVE: Bipolar disorder often co-occurs with other axis I disorders, but little is known about the relationships between the clinical features of bipolar illness and these comorbid conditions. Therefore, the authors assessed comorbid lifetime and current axis I disorders in 288 patients with bipolar disorder and the relationships of these comorbid disorders to selected demographic and historical illness variables. METHOD: They evaluated 288 outpatients with bipolar I or II disorder, using structured diagnostic interviews and clinician-administered and self-rated questionnaires to determine the diagnosis of bipolar disorder, comorbid axis I disorder diagnoses, and demographic and historical illness characteristics. RESULTS: One hundred eighty-seven (65%) of the patients with bipolar disorder also met DSM-IV criteria for at least one comorbid lifetime axis I disorder. More patients had comorbid anxiety disorders (N=78, 42%) and substance use disorders (N=78, 42%) than had eating disorders (N=9, 5%). There were no differences in comorbidity between patients with bipolar I and bipolar II disorder. Both lifetime axis I comorbidity and current axis I comorbidity were associated with earlier age at onset of affective symptoms and syndromal bipolar disorder. Current axis I comorbidity was associated with a history of development of both cycle acceleration and more severe episodes over time. CONCLUSIONS: Patients with bipolar disorder often have comorbid anxiety, substance use, and, to a lesser extent, eating disorders. Moreover, axis I comorbidity, especially current comorbidity, may be associated with an earlier age at onset and worsening course of bipolar illness. Further research into the prognostic and treatment response implications of axis I comorbidity in bipolar disorder is important and is in progress.