Debra Glitz

Lithium increases N-acetyl-aspartate in the human brain: in vivo evidence in support of bcl-2’s neurotrophic effects?

BACKGROUND Recent preclinical studies have shown that lithium (Li) robustly increases the levels of the major neuroprotective protein, bcl-2, in rat brain and in cells of human neuronal origin. These effects are accompanied by striking neuroprotective effects in vitro and in the rodent central nervous system in vivo. We have undertaken the present study to determine if lithium exerts neurotrophic/ neuroprotective effects in the human brain in vivo. METHODS Using quantitative proton magnetic resonance spectroscopy, N-acetyl-aspartate (NAA) levels (a putative marker of neuronal viability and function) were investigated longitudinally in 21 adult subjects (12 medication-free bipolar affective disorder patients and 9 healthy volunteers). Regional brain NAA levels were measured at baseline and following 4 weeks of lithium (administered in a blinded manner). RESULTS A significant increase in total brain NAA concentration was documented (p < .0217). NAA concentration increased in all brain regions investigated, including the frontal, temporal, parietal, and occipital lobes. CONCLUSIONS This study demonstrates for the first time that Li administration at therapeutic doses increases brain NAA concentration. These findings provide intriguing indirect support for the contention that chronic lithium increases neuronal viability/function in the human brain, and suggests that some of Lis long-term beneficial effects may be mediated by neurotrophic/neuroprotective events.

Decreased heart rate variability in panic disorder patients: A study of power-spectral analysis of heart rate

We have previously found decreased standard deviations and mean consecutive differences of R-R intervals in panic disorder patients in standing posture, compared with control subjects. In the present study, we used spectral analysis of heart rate variability to examine autonomic function in 21 panic disorder patients and 21 normal control subjects. Patients had a significantly lower standard deviation of heart rate in supine as well as standing postures. Absolute low frequency power (0.01-0.05 Hz) was also significantly lower in panic disorder patients in standing postures. Upon standing, the panic disorder patients had significantly higher relative mid-frequency power (0.07-0.15 Hz). During a standing deep-breathing condition at six breaths per minute, the patients had a significantly decreased absolute and relative mid-frequency (0.07-0.15 Hz) power compared with control subjects. These findings suggest a decrease in cholinergic and a relative increase in adrenergic responsiveness in panic disorder patients compared with control subjects.

Heart Rate Variability in Patients With Major Depression

We have previously reported decreased heart rate variability upon standing in panic disorder patients compared with controls. In this study, we extend our report to include patients with major depression (n = 19). Compared to normal controls (n = 20) and panic disorder patients (n = 30), there was no significant difference in the immediate changes in heart rate upon standing in the depressed group. The standing heart rate variability (R-R variability) was significantly lower in panic disorder patients compared to both normal controls and depressed patients as indicated by the corrected standard deviations, the corrected mean consecutive difference, the corrected standard deviation of the mean consecutive difference of the R-R intervals, and the high frequency variability in successive R-R intervals, suggesting an increased vagal withdrawal in panic disorder patients, especially upon standing. There was no significant difference in any of the heart rate variability measures between depressed patients and normal controls.

Genomewide Linkage Analyses of Bipolar Disorder: A New Sample of 250 Pedigrees from the National Institute of Mental Health Genetics Initiative

We conducted genomewide linkage analyses on 1,152 individuals from 250 families segregating for bipolar disorder and related affective illnesses. These pedigrees were ascertained at 10 sites in the United States, through a proband with bipolar I affective disorder and a sibling with bipolar I or schizoaffective disorder, bipolar type. Uniform methods of ascertainment and assessment were used at all sites. A 9-cM screen was performed by use of 391 markers, with an average heterozygosity of 0.76. Multipoint, nonparametric linkage analyses were conducted in affected relative pairs. Additionally, simulation analyses were performed to determine genomewide significance levels for this study. Three hierarchical models of affection were analyzed. Significant evidence for linkage (genomewide P<.05) was found on chromosome 17q, with a peak maximum LOD score of 3.63, at the marker D17S928, and on chromosome 6q, with a peak maximum LOD score of 3.61, near the marker D6S1021. These loci met both standard and simulation-based criteria for genomewide significance. Suggestive evidence of linkage was observed in three other regions (genomewide P<.10), on chromosomes 2p, 3q, and 8q. This study, which is based on the largest linkage sample for bipolar disorder analyzed to date, indicates that several genes contribute to bipolar disorder.

A longitudinal study of the effects of lithium treatment on prefrontal and subgenual prefrontal gray matter volume in treatment-responsive bipolar disorder patients.

OBJECTIVE Recent molecular, preclinical, and preliminary clinical studies suggest that the therapeutic effects of mood stabilizers may be mediated by modulating expression of potent neurotrophic and neuroprotective factors having the potential to reverse impairments of cellular resilience, reductions in brain volume, and cell death or atrophy. Our main goal was to investigate the potential clinical significance of these findings in relation to bipolar disorder. METHOD The longitudinal effect of lithium on brain gray matter volume was investigated in well-characterized (DSM-IV criteria) bipolar depressed subjects (N = 28) at baseline (medication-free) and after lithium administration (4 weeks). Total brain gray matter, prefrontal gray matter, and left subgenual prefrontal gray matter volumes were determined using validated semiautomated segmentation and region of interest methodology. The study was conducted from November 1997 until April 2004 at Wayne State University School of Medicine, Detroit, Mich. RESULTS Significant increases in total brain gray matter volume in bipolar subjects were observed after 4 weeks of lithium administration (p = .0043). Moreover, regional analyses in the bipolar subjects revealed significant differences between responders (>50% decrease in Hamilton Depression Rating Scale total score) and nonresponders; only responders showed a significant increase in gray matter volume in the prefrontal cortex (p = .003) and an increase at trend level in the left subgenual prefrontal cortex volume (p = .0786). CONCLUSION The increase in gray matter volume in these areas, which various neuroimaging and postmortem neuropathology studies have implicated in the neuropathophysiology of bipolar disorder, suggests that the observed effects may be linked to clinical response. The findings also support the notion that future treatments that more directly target molecules in critical central nervous system pathways that regulate cellular plasticity hold promise as novel, improved, long-term treatments for mood disorders as well as some neurodegenerative conditions, such as Alzheimers disease. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00870311.

Family-based association of FKBP5 in bipolar disorder.

The FKBP5 gene product forms part of a complex with the glucocorticoid receptor and can modulate cortisol-binding affinity. Variations in the gene have been associated with increased recurrence of depression and with rapid response to antidepressant treatment. We sought to determine whether common FKBP5 variants confer risk for bipolar disorder. We genotyped seven tag single-nucleotide polymorphisms (SNPs) in FKBP5, plus two SNPs previously associated with illness, in 317 families with 554 bipolar offspring, derived primarily from two studies. Single marker and haplotypic analyses were carried out with FBAT and EATDT employing the standard bipolar phenotype. Association analyses were also conducted using 11 disease-related variables as covariates. Under an additive genetic model, rs4713902 showed significant overtransmission of the major allele (P=0.0001), which was consistent across the two sample sets (P=0.004 and 0.006). rs7757037 showed evidence of association that was strongest under the dominant model (P=0.001). This result was consistent across the two datasets (P=0.017 and 0.019). The dominant model yielded modest evidence for association (P<0.05) for three additional markers. Covariate-based analyses suggested that genetic variation within FKBP5 may influence attempted suicide and number of depressive episodes in bipolar subjects. Our results are consistent with the well-established relationship between the hypothalamic–pituitary–adrenal (HPA) axis, which mediates the stress response through regulation of cortisol, and mood disorders. Ongoing whole-genome association studies in bipolar disorder and major depression should further clarify the role of FKBP5 and other HPA genes in these illnesses.

Regulation of signal transduction pathways and gene expression by mood stabilizers and antidepressants.

OBJECTIVE To determine whether the currently available evidence supports the hypothesis that antidepressants and mood stabilizers may bring about some of their long-term therapeutic effects by regulating signal transduction pathways and gene expression in the central nervous system. METHODS To address this question, we reviewed the evidence showing that chronic administration of antidepressants and mood stabilizers involves alterations in signaling pathways and gene expression in the central nervous system. RESULTS A large body of data has shown that lithium and valproate exert effects on the protein kinase C signaling pathway and the activator protein 1 family of transcription factors; in contrast, antidepressants affect the cyclic adenosine monophosphate pathway and may bring about their therapeutic effects by modulating cyclic adenosine monophosphate-regulated gene expression in the central nervous system. CONCLUSIONS Given the key roles of these signaling cascades in the amplification and integration of signals in the central nervous system, the findings have clear implications not only for research into the etiology and pathophysiology of the severe mood disorders but also for the development of novel and innovative treatment strategies.

Effect of imipramine treatment on heart rate variability measures

Recently, heart rate (HR) variability has received considerable attention, and a decreased HR variability has been linked to a significant risk of cardiovascular illness. We have previously reported such a decreased variability in panic disorder patients. In this study, we report on HR variability in 12 depressed and 6 panic disorder patients at baseline and 1 and 3 weeks of treatment with imipramine as measured by the standard deviation, mean consecutive difference and the standard deviation of the mean consecutive difference of the R-R intervals in supine, supine deep breathing and standing postures. In all subjects, imipramine (mean dose: 70 mg/day) produced a significant decrease in heart rate variability at week 3 as measured by the above variables. This decrease in HR variability during imipramine treatment is probably due to its anticholinergic effects.

Risk Factors for Cardiovascular Illness in Panic Disorder Patients

Supine and standing heart rate (HR) and blood pressure measures were compared among 19 nonsmoking normal controls, 29 smoking patients and 36 nonsmoking patients with panic disorder. The smoking patients had a significantly higher supine HR, standing diastolic blood pressure, standing mean blood pressure and supine and standing cardiac load measures compared to both patient nonsmokers and controls. There was no significant difference between controls and nonsmoking patients for any of the above measures except for the higher standing HR and the delta increase in HR upon standing in female panic disorder patients which suggests increased adrenergic activity. When lipid values of panic disorder patients (n = 92) were compared to National Reference Values for their sex and age for an increased risk of cardiovascular illness, there was no significant risk with regard to plasma levels of total cholesterol, high-density lipoprotein cholesterol or low-density lipoprotein cholesterol.

Heart rate time series: decreased chaos after intravenous lactate and increased non-linearity after isoproterenol in normal subjects

In this study, we reanalyzed our previous heart rate time series data on the effects of intravenous sodium lactate (n=9) and intravenous isoproterenol (n=11) using non-linear techniques. Our prior findings of significantly higher baseline non-linear scores (NL: S(netGS)) and significantly lower largest Lyapunov exponents in supine posture in patients with panic disorder compared to control subjects prompted this study. We obtained the largest Lyapunov exponent (LLE), and a measure of non-linearity (NL: S(netGS)) of heart rate time series. LLE quantifies predictability and NL quantifies the deviation from linear processes. There was a significant increase in NL score, (S(netGS)) after isoproterenol infusions and a significant decrease in LLE (an increase in predictability indicating decreased chaos), after intravenous lactate in supine posture in normal control subjects. Increased NL scores in supine posture after intravenous isoproterenol may be due to a relative increase in cardiac sympathetic activity or a decrease in vagal activity at least in certain circumstances, and an overall decrease in LLE may indicate an impaired cardiac autonomic flexibility after intravenous sodium lactate, as LLE is diminished by autonomic blockade by atropine. Band analysis of LLE (LF/HF) (LF: 0.04-0.15 Hz and HF: 0.15-0.5 Hz) showed an increase of these ratios during either condition with a higher sympathovagal interaction after the drug administration. These findings may throw new light on the association of anxiety and significant cardiovascular events.