Detailed assessment of suicidal ideation in youth with bipolar disorder versus major depressive disorder.

OBJECTIVES: There is a critical need to better understand the factors underlying the increased suicide risk for youth with bipolar disorder (BD) in order to develop targeted prevention efforts. This study aimed to examine differences in characteristics of suicide ideation (SI) in youth with BD compared to youth with major depressive disorder (MDD) that may be associated with increased suicide risk. METHODS: One hundred and fifty-one participants (92 MDD and 59 BD), ages 13-21, completed a diagnostic interview and clinical assessments. Lifetime symptoms of SI and SA were assessed using the Columbia Suicide Severity Rating Scale. Ordinal logistic regression models were used to investigate whether the diagnostic group predicted the severity and intensity of the most severe or most common SI with the age of onset, age, and gender as covariates. RESULTS: Compared to MDD youth, BD youth were more likely to report experiencing more severe SI, p = 0.039, experiencing the most severe SI more frequently, p = 0.002, having less control of the most severe SI, p = 0.012, and that deterrents were less likely to stop them from acting on the most severe SI, p = 0.006. CONCLUSION: This study highlights differences in the severity and intensity of SI in youth with BD and suggests that youth with BD have greater difficulty inhibiting thoughts of SI which may lead to less resistance to suicide action. Findings underscore the need for a more detailed assessment of SI in youth with BD to better understand SI as a proximal risk factor for future SA and a potential target for intervention.

Creatine for the Treatment of Depression.

Depressed mood, which can occur in the context of major depressive disorder, bipolar disorder, and other conditions, represents a serious threat to public health and wellness. Conventional treatments are not effective for a significant proportion of patients and interventions that are often beneficial for treatment-refractory depression are not widely available. There is, therefore, an immense need to identify novel antidepressant strategies, particularly strategies that target physiological pathways that are distinct from those addressed by conventional treatments. There is growing evidence from human neuroimaging, genetics, epidemiology, and animal studies that disruptions in brain energy production, storage, and utilization are implicated in the development and maintenance of depression. Creatine, a widely available nutritional supplement, has the potential to improve these disruptions in some patients, and early clinical trials indicate that it may have efficacy as an antidepressant agent.

Effect of Altitude on Veteran Suicide Rates.

Aims: Suicide rates in the general population in the United States are correlated with altitude. To explore factors contributing to suicide among military veterans, we examined the relationship between veteran state-level suicide rates and altitude for 2014, including firearm-related and nonfirearm-related rates. Methods: Pearson's coefficients were calculated for altitude and each outcome. Mixed linear models were used to determine the association between suicide and altitude while adjusting for demographic confounds. Results: State mean altitude was significantly correlated with total veteran suicide rate (r = 0.678, p < 0.0001), veteran firearm-related suicide rate (r = 0.578, p < 0.0001), and veteran nonfirearm suicide rate (r = 0.609, p < 0.0001). In mixed models, altitude was significantly correlated with total veteran suicide rate (ß = 0.331, p < 0.05), veteran firearm suicides (ß = 0.282, p < 0.05), and veteran nonfirearm suicides (ß = 0.393, p < 0.05). Conclusion: This study adds to evidence linking altitude and suicide rates, arguing for additional research into the relationship between altitude and suicide among veterans.

Reduced lateral orbitofrontal cortex volume and suicide behavior in youth with bipolar disorder.

OBJECTIVES: Structural abnormalities in cortical and subcortical regions, including the orbitofrontal cortex (OFC), are altered during brain development in adolescents with bipolar disorder (BD), which may increase risk for suicide. Few studies have examined the neural substrates of suicidal behavior in BD youth. The aim of the present study was to investigate the relationship between suicide behavior and the OFC in youth with BD. METHODS: Thirty-seven participants with BD and 26 non-psychiatric controls, ages 13-21 years, completed a diagnostic interview and mood rating scales. Lifetime symptoms of suicide ideation and behavior were examined using the Columbia Suicide Severity Rating Scale. Participants underwent magnetic resonance imaging on a 3T Siemens Verio scanner. Morphometric analysis of brain images was performed using FreeSurfer. RESULTS: Eighteen participants with BD had a history of suicide attempt (SA). Bipolar youth with a history of SA showed reduced left lateral OFC volumes compared to controls, but there was no difference between BD attempters and non-attempters. Controls and BD non-attempters had significantly greater OFC cortical thickness than BD attempters. Additionally, there was a significant negative correlation between OFC volumes and suicide lethality, demonstrating that as suicide lethality increased, OFC volume in BD youth was reduced. CONCLUSIONS: The OFC is involved in decision-making, impulsivity, and reward circuitry which have shown to be impaired in BD. Reduced OFC volume and its association with lethality of suicide suggest that suicide behavior in BD may be related to the emerging neuroanatomical substrates of the disorder, particularly abnormalities of the OFC.

Two-Dimensional Proton Magnetic Resonance Spectroscopy versus J-Editing for GABA Quantification in Human Brain: Insights from a GABA-Aminotransferase Inhibitor Study.

Metabolite-specific, scalar spin-spin coupling constant (J)-editing 1H MRS methods have become gold-standard for measuring brain γ-amino butyric acid (GABA) levels in human brain. Localized, two-dimensional (2D) 1H MRS technology offers an attractive alternative as it significantly alleviates the problem of severe metabolite signal overlap associated with standard 1D MRS and retains spectroscopic information for all MRS-detectable species. However, for metabolites found at low concentration, a direct, in vivo, comprehensive methods comparison is challenging and has not been reported to date. Here, we document an assessment of comparability between 2D 1H MRS and J-editing methods for measuring GABA in human brain. This clinical study is unique in that it involved chronic administration a GABA-amino transferase (AT) inhibitor (CPP-115), which induces substantial increases in brain GABA concentration, with normalization after washout. We report a qualitative and quantitative comparison between these two measurement techniques. In general, GABA concentration changes detected using J-editing were closely mirrored by the 2D 1H MRS time courses. The data presented are particularly encouraging considering recent 2D 1H MRS methodological advances are continuing to improve temporal resolution and spatial coverage for achieving whole-brain, multi-metabolite mapping.

Living High and Feeling Low: Altitude, Suicide, and Depression.

LEARNING OBJECTIVES: After participating in this activity, learners should be better able to:• Assess epidemiologic evidence that increased altitude of residence is linked to increased risk of depression and suicide• Evaluate strategies to address hypoxia-related depression and suicidal ideation ABSTRACT: Suicide and major depressive disorder (MDD) are complex conditions that almost certainly arise from the influences of many interrelated factors. There are significant regional variations in the rates of MDD and suicide in the United States, suggesting that sociodemographic and environmental conditions contribute. Here, we review epidemiological evidence that increases in the altitude of residence are linked to the increased risk of depression and suicide. We consider the possibility that chronic hypobaric hypoxia (low blood oxygen related to low atmospheric pressure) contributes to suicide and depression, which is suggested by animal models, short-term studies in humans, and the effects of hypoxic medical conditions on suicide and depression. We argue that hypobaric hypoxia could promote suicide and depression by altering serotonin metabolism and brain bioenergetics; both of these pathways are implicated in depression, and both are affected by hypoxia. Finally, we briefly examine treatment strategies to address hypoxia-related depression and suicidal ideation that are suggested by these findings, including creatine monohydrate and the serotonin precursors tryptophan and 5-hydroxytryptophan.

Association Between Altitude and Regional Variation of ADHD in Youth.

OBJECTIVE: The purpose of this study was to evaluate the effect of altitude on rates of ADHD. As decreased dopamine (DA) activity has been reported with ADHD and hypoxia has shown to be associated with increased DA, we hypothesized that states at higher altitudes would have lower rates of ADHD. METHOD: State estimates from the 2007 National Survey of Children's Health (NSCH) report and 2010 National Survey of Children with Special Health Care Needs (NS-CSHCN) report were used to extract the percentages of youth ages 4 to 17 diagnosed with ADHD. RESULTS: Both the datasets independently revealed that the prevalence of ADHD decreases with increasing altitude ( R2 = .38, p < .001; R2 = .31, p < .001), respectively. This study controlled for potential confounds (e.g., low birth weight, ethnicity, and household size). CONCLUSION: These findings suggest a need for further investigation into the extent by which altitude may serve as a protective factor for ADHD.

Relationship of executive functioning deficits to N-acetyl aspartate (NAA) and gamma-aminobutyric acid (GABA) in youth with bipolar disorder.

BACKGROUND: Although cognitive deficits in bipolar disorder (BD) have been repeatedly observed, our understanding of these impairments at a mechanistic level remains limited. Few studies that investigated cognitive impairments in bipolar illness have examined the association with brain biochemistry. This pilot study utilized proton magnetic resonance spectroscopy (1H-MRS) to evaluate the relationship between neurocognitive performance and brain metabolites in youth with BD. METHODS: Thirty participants, twenty depressed BD participants and ten healthy comparison participants, ages 13-21, completed mood and executive function measures. 1H-MRS data were also acquired from the anterior cingulate cortex (ACC) using two-dimensional (2D) J-resolved 1H-MRS sequence. Proton metabolites including N-acetyl aspartate (NAA) and gamma-aminobutyric acid (GABA) were quantified for both groups. RESULTS: Participants with BD performed significantly lower on executive functioning measures than comparison participants. There were significant positive correlations between Wisconsin Card Sorting Test (WCST) performance and NAA (p < .001) and GABA (p < .01) in the ACC in bipolar youth, such that as WCST performance increased, both NAA and GABA levels increased. LIMITATIONS: Small sample size and lack of control for medications. CONCLUSIONS: These findings build on previous observations of biochemical alterations associated with BD and indicate that executive functioning deficits in bipolar youth are correlated with NAA and GABA. These results suggest that cognitive deficits occur early in the course of illness and may reflect risk factors associated with altered neurochemistry. Further investigation of the relationship between brain metabolites and cognition in BD may lead to important information for developing novel, targeted interventions.

In Vivo Detection of CPP-115 Target Engagement in Human Brain.

CPP-115, a next-generation γ-amino butyric acid (GABA)-aminotransferase (AT) inhibitor, shows comparable pharmacokinetics, improved safety and tolerability, and a more favorable toxicity profile when compared with vigabatrin. The pharmacodynamic characteristics of CPP-115 remain to be evaluated. The present study employed state-of-the-art proton magnetic resonance spectroscopy techniques to measure changes in brain GABA+ (the composite resonance of GABA, homocarnosine, and macromolecules) concentrations in healthy subjects receiving oral daily doses of CPP-115 or placebo. Six healthy adult males were randomized to receive either single daily 80 mg doses of CPP-115 (n=4) or placebo (n=2) for 6, 10, or 14 days. Metabolite-edited spectra and two-dimensional J-resolved spectroscopy data were acquired from the parietal-occipital cortex and supplementary motor area in all subjects. Four scans were performed in each subject that included a predrug baseline measure, two scans during the dosing timeframe, and a final scan that occurred 1 week after drug cessation. CPP-115 induced robust and significant increases in brain GABA+ concentrations that ranged between 52 and 141% higher than baseline values. Elevated GABA+ concentrations returned to baseline values following drug clearance. Subjects receiving placebo showed no significant changes in GABA+ concentration. CPP-115-induced changes were exclusive to GABA and homocarnosine, and CPP-115 afforded brain GABA+ concentration changes comparable to or greater than previous vigabatrin spectroscopy studies in healthy epilepsy-naive subjects. The return to baseline GABA+ concentration indicates the reversible GABA-AT resynthesis following drug washout. These preliminary data warrant further spectroscopy studies that characterize the acute pharmacodynamic effects of CPP-115 with additional dose-descending measures.

An Open-Label Pilot Study of Combined Augmentation With Creatine Monohydrate and 5-Hydroxytryptophan for Selective Serotonin Reuptake Inhibitor- or Serotonin-Norepinephrine Reuptake Inhibitor-Resistant Depression in Adult Women.

PURPOSE: Many women with major depressive disorder (MDD) respond inadequately to standard treatments. Augmentation of conventional antidepressants with creatine monohydrate and 5-hydroxytryptophan (5-HTP) could correct deficits in serotonin production and brain bioenergetics associated with depression in women, yielding synergistic benefit. We describe an open-label study of 5-HTP and creatine augmentation in women with MDD who had failed selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI) monotherapy. METHODS: Fifteen women who were adequately adherent to an SSRI or SNRI and currently experiencing MDD, with a 17-item Hamilton Depression Rating Scale (HAM-D) score of 16 or higher, were treated with 5 g of creatine monohydrate daily and 100 mg of 5-HTP twice daily for 8 weeks, with 4 weeks of posttreatment follow-up. The primary outcome was change in mean HAM-D scores. RESULTS: Mean HAM-D scores declined from 18.9 (SD, 2.5) at pretreatment visits to 7.5 (SD, 4.4) (P < 0.00001), a decrease of 60%. Participants did not experience any serious treatment-related adverse events. CONCLUSIONS: Combination treatment with creatine and 5-HTP may represent an effective augmentation strategy for women with SSRI- or SNRI-resistant depression. Given the limitations of this small, open-label trial, future study in randomized, placebo-controlled trials is warranted.

Creatine target engagement with brain bioenergetics: a dose-ranging phosphorus-31 magnetic resonance spectroscopy study of adolescent females with SSRI-resistant depression.

Major depressive disorder (MDD) often begins during adolescence and is projected to become the leading cause of global disease burden by the year 2030. Yet, approximately 40 % of depressed adolescents fail to respond to standard antidepressant treatment with a selective serotonin reuptake inhibitor (SSRI). Converging evidence suggests that depression is related to brain mitochondrial dysfunction. Our previous studies of MDD in adult and adolescent females suggest that augmentation of SSRI pharmacotherapy with creatine monohydrate (CM) may improve MDD outcomes. Neuroimaging with phosphorus-31 magnetic resonance spectroscopy ((31)P-MRS) can measure the high-energy phosphorus metabolites in vivo that reflect mitochondrial function. These include phosphocreatine (PCr), a substrate for the creatine kinase reaction that produces adenosine triphosphate. As part of the National Institute of Mental Health's experimental medicine initiative, we conducted a placebo-controlled dose-ranging study of adjunctive CM for adolescent females with SSRI-resistant MDD. Participants were randomized to receive placebo or CM 2, 4 or 10 g daily for 8 weeks. Pre- and post-treatment (31)P-MRS scans were used to measure frontal lobe PCr, to assess CM's target engagement with cerebral energy metabolism. Mean frontal lobe PCr increased by 4.6, 4.1 and 9.1 % in the 2, 4 and 10 g groups, respectively; in the placebo group, PCr fell by 0.7 %. There was no group difference in adverse events, weight gain or serum creatinine. Regression analysis of PCr and depression scores across the entire sample showed that frontal lobe PCr was inversely correlated with depression scores (p = 0.02). These results suggest that CM achieves target engagement with brain bioenergetics and that the target is correlated with a clinical signal. Further study of CM as a treatment for adolescent females with SSRI-resistant MDD is warranted.

Decreased brain PME/PDE ratio in bipolar disorder: a preliminary (31) P magnetic resonance spectroscopy study.

OBJECTIVES: The aim of the present study was to measure brain phosphorus-31 magnetic resonance spectroscopy ((31) P MRS) metabolite levels and the creatine kinase reaction forward rate constant (kf ) in subjects with bipolar disorder (BD). METHODS: Subjects with bipolar euthymia (n = 14) or depression (n = 11) were recruited. Healthy comparison subjects (HC) (n = 23) were recruited and matched to subjects with BD on age, gender, and educational level. All studies were performed on a 3-Tesla clinical magnetic resonance imaging system using a (31) P/(1) H double-tuned volume head coil. (31) P spectra were acquired without (1) H-decoupling using magnetization-transfer image-selected in vivo spectroscopy. Metabolite ratios from a brain region that includes the frontal lobe, corpus callosum, thalamus, and occipital lobe are expressed as a percentage of the total phosphorus (TP) signal. Brain pH was also investigated. RESULTS: Beta-nucleoside-triphosphate (ß-NTP/TP) in subjects with bipolar depression was positively correlated with kf (p = 0.039, r(2) = 0.39); similar correlations were not observed in bipolar euthymia or HC. In addition, no differences in kf and brain pH were observed among the three diagnostic groups. A decrease in the ratio of phosphomonoesters to phosphodiesters (PME/PDE) was observed in subjects with bipolar depression relative to HC (p = 0.032). We also observed a trend toward an inverse correlation in bipolar depression characterized by decreased phosphocreatine and increased depression severity. CONCLUSIONS: In our sample, kf was not altered in the euthymic or depressed mood state in BD. However, decreased PME/PDE in subjects with bipolar depression was consistent with differences in membrane turnover. These data provide preliminary support for alterations in phospholipid metabolism and mitochondrial function in bipolar depression.

Gender differences in the effect of tobacco use on brain phosphocreatine levels in methamphetamine-dependent subjects.

BACKGROUND: A high prevalence of tobacco smoking has been observed in methamphetamine users, but there have been no in vivo brain neurochemistry studies addressing gender effects of tobacco smoking in methamphetamine users. Methamphetamine addiction is associated with increased risk of depression and anxiety in females. There is increasing evidence that selective analogues of nicotine, a principal active component of tobacco smoking, may ease depression and improve cognitive performance in animals and humans. OBJECTIVES: To investigate the effects of tobacco smoking and gender on brain phosphocreatine (PCr) levels, a marker of brain energy metabolism reported to be reduced in methamphetamine-dependent subjects. METHODS: Thirty female and 27 male methamphetamine-dependent subjects were evaluated with phosphorus-31 magnetic resonance spectroscopy ((31)P-MRS) to measure PCr levels within the pregenual anterior cingulate, which has been implicated in methamphetamine neurotoxicity. RESULTS: Analysis of covariance revealed that there were statistically significant slope (PCr versus lifetime amount of tobacco smoking) differences between female and male methamphetamine-dependent subjects (p = 0.03). In females, there was also a statistically significant interaction between lifetime amounts of tobacco smoking and methamphetamine in regard to PCr levels (p = 0.01), which suggests that tobacco smoking may have a more significant positive impact on brain PCr levels in heavy, as opposed to light to moderate, methamphetamine-dependent females. CONCLUSION: These results indicate that tobacco smoking has gender-specific effects in terms of increased anterior cingulate high energy PCr levels in methamphetamine-dependent subjects. Cigarette smoking in methamphetamine-dependent women, particularly those with heavy methamphetamine use, may have a potentially protective effect upon neuronal metabolism.

Relationship between altitude and lithium in groundwater in the United States of America: results of a 1992-2003 study.

Therapeutic dosages of lithium are known to reduce suicide rates, which has led to investigations of confounding environmental risk factors for suicide such as lithium in groundwater. It has been speculated that this might play a role in the potential relationship between suicide and altitude. A recent study in Austria involving geospatial analysis of lithium in groundwater and suicide found lower levels of lithium at higher altitudes. Since there is no reason to suspect this correlation is universal given variation in geology, the current study set out to investigate the relationship between altitude and lithium in groundwater in the United States of America (USA). The study utilised data extracted from the National Water-Quality Assessment programme implemented by the United States Geological Survey that has collected 5,183 samples from 48 study areas in USA for the period of 1992 to 2003. Lithium was the trace-element of interest and 518 samples were used in the current analyses. Due to uneven lithium sampling within the country, only the states (n=15) with the highest number of lithium samples were included. Federal information processing standard codes were used to match data by county with the mean county altitude calculated using altitude data from the Shuttle Radar Topography Mission. The study was controlled for potential confounding factors known to affect levels of lithium in groundwater including aquifer, aquifer type, lithology, water level and the depths of wells. The levels of lithium in groundwater, increased with altitude (R(2) = 0.226, P <0.001) during the study period. These findings differ from the Austrian study and suggest a need for further research accounting also for the impact of geographical variation.

Altitude may contribute to regional variation in methamphetamine use in the United States: a population database study.

OBJECTIVE: Methamphetamine (MA) use rates in the United States (US) have consistently demonstrated geographical variation and have been higher in the West and Midwest. This uneven pattern of use could be explained by regional differences in MA manufacturing and distribution, but may also result from differences in altitude. The hypobaric hypoxia found at high altitude alters neurotransmitter synthesis in the brain, which may contribute to MA use. The present study investigated the relationship between mean altitude and MA use rate in the 48 contiguous US states and the District of Columbia. METHODS: State-level estimates of past year MA use were extracted from the National Survey on Drug Use and Health report. The mean altitude of each state was calculated using the Shuttle Radar Topography Mission altitude data set. RESULTS: There was a significant positive correlation between mean state altitude and MA use rate (r=0.66, p<0.0001). Multivariate linear regression analysis showed that altitude remained a significant predictor for MA use rate (ß=0.36, p=0.02), after adjusting for age, ethnicity, education, socioeconomic level, employment, MA laboratory incidents, subpopulations, and other substance use. CONCLUSION: Altitude appears to a possible contributing factor for regional variation of MA use in the US. Further studies will be required to determine biological changes in neurotransmission resulting from chronic mild hypoxia at high altitude in MA users.

Anterior cingulate cortex choline levels in female adolescents with unipolar versus bipolar depression: a potential new tool for diagnosis.

BACKGROUND: Delayed diagnosis in bipolar disorder (BD) due to misdiagnosis as major depressive disorder (MDD) is a significant public health concern. Thus, identification of relevant diagnostic biomarkers is a critical unmet need, particularly early in the course of illness. The anterior cingulate cortex (ACC) is thought to play an important role in mood disorder pathophysiology. Case-control studies utilizing proton-1 magnetic resonance spectroscopy ((1)H-MRS) have found increased total choline levels in several brain regions in MDD. However, there are no published (1)H-MRS reports directly comparing adolescents with MDD and BD. We hypothesized that ACC choline levels would be increased in adolescents with unipolar versus bipolar depression. METHODS: We studied depressed adolescents with MDD (n=28; mean age 17.0±2.1 years) and BD (n=9; 17.3±3.1 years). A Siemens Verio 3-Tesla clinical MRI system was used to acquire scans, using a single-voxel PRESS sequence. The voxel (18.75 cm(3)) was positioned on the ACC in the midsagittal plane. To remove potential gender effects, only female adolescent participants were included. Data were analyzed using the ANOVA and post-hoc Tukey tests. RESULTS: A significantly increased ACC choline/creatine ratio was observed in participants with MDD (mean=0.253±0.021) compared to BD (mean=0.219±0.020) (p=0.0002). There were no significant differences in the other (1)H-MRS metabolites. LIMITATIONS: Cross sectional design, single gender sample, limited sample size. CONCLUSIONS: The present findings suggest that ACC total choline may have the potential to serve as a diagnostic biomarker in adolescent mood disorders.

Effect of altitude on brain intracellular pH and inorganic phosphate levels.

Normal brain activity is associated with task-related pH changes. Although central nervous system syndromes associated with significant acidosis and alkalosis are well understood, the effects of less dramatic and chronic changes in brain pH are uncertain. One environmental factor known to alter brain pH is the extreme, acute change in altitude encountered by mountaineers. However, the effect of long-term exposure to moderate altitude has not been studied. The aim of this two-site study was to measure brain intracellular pH and phosphate-bearing metabolite levels at two altitudes in healthy volunteers, using phosphorus-31 magnetic resonance spectroscopy ((31)P-MRS). Increased brain pH and reduced inorganic phosphate (Pi) levels were found in healthy subjects who were long-term residents of Salt Lake City, UT (4720ft/1438m), compared with residents of Belmont, MA (20ft/6m). Brain intracellular pH at the altitude of 4720ft was more alkaline than that observed near sea level. In addition, the ratio of inorganic phosphate to total phosphate signal also shifted toward lower values in the Salt Lake City region compared with the Belmont area. These results suggest that long-term residence at moderate altitude is associated with brain chemical changes.

Altitude is a risk factor for completed suicide in bipolar disorder.

Bipolar disorder (BD) is a severe brain disease that is associated with a significant risk for suicide. Recent studies indicate that altitude of residence significantly affects overall rate of completed suicide, and is associated with a higher incidence of depressive symptoms. Bipolar disorder has shown to be linked to mitochondrial dysfunction that may increase the severity of episodes. The present study used existing data sets to explore the hypothesis that altitude has a greater effect of suicide in BD, compared with other mental illnesses. The study utilized data extracted from the National Violent Death Reporting System (NVDRS), a surveillance system designed by the Centers for Disease Control and Prevention (CDC) National Center for Injury Prevention and Control (NCIPC). Data were available for 16 states for the years 2005-2008, representing a total of 35,725 completed suicides in 922 U.S. counties. Random coefficient and logistic regression models in the SAS PROC MIXED procedure were used to estimate the effect of altitude on decedent's mental health diagnosis. Altitude was a significant, independent predictor of the altitude at which suicides occurred (F=8.28, p=0.004 and Wald chi-square=21.67, p<0.0001). Least squares means of altitude, independent of other variables, indicated that individuals with BD committed suicide at the greatest mean altitude. Moreover, the mean altitude at which suicides occurred in BD was significantly higher than in decedents whose mental health diagnosis was major depressive disorder (MDD), schizophrenia, or anxiety disorder. Identifying diagnosis-specific risk factors such as altitude may aid suicide prevention efforts, and provide important information for improving the clinical management of BD.

Decreased frontal lobe phosphocreatine levels in methamphetamine users.

BACKGROUND: Mitochondria-related mechanisms have been suggested to mediate methamphetamine (METH) toxicity. However, changes in brain energetics associated with high-energy phosphate metabolism have not been investigated in METH users. Phosphorus-31 ((31)P) magnetic resonance spectroscopy (MRS) was used to evaluate changes in mitochondrial high energy phosphates, including phosphocreatine (PCr) and ß-nucleoside triphosphate (ß-NTP, primarily ATP in brain) levels. We hypothesized that METH users would have decreased high-energy PCr levels in the frontal gray matter. METHODS: Study participants consisted of 51 METH (age=32.8±6.7) and 23 healthy comparison (age=31.1±7.5) subjects. High-energy phosphate metabolite levels were compared between the groups and potential gender differences were explored. RESULTS: METH users had lower ratios of PCr to total pool of exchangeable phosphate (PCr/TPP) in the frontal lobe as compared to the healthy subjects (p=.001). The lower PCr levels in METH subjects were significantly associated with lifetime amount of METH use (p=.003). A sub-analysis for gender differences revealed that female METH users, who had lower daily amounts (1.1±1.0g) of METH use than males (1.4±1.7g), had significantly lower PCr/TPP ratios than male METH users, controlling for the amount of METH use (p=.02). CONCLUSIONS: The present findings suggest that METH compromises frontal lobe high-energy phosphate metabolism in a dose-responsive manner. Our findings also suggest that the abnormality in frontal lobe high-energy phosphate metabolism might be more prominent in female than in male METH users. This is significant as decreased PCr levels have been associated with depressive symptoms, and poor responses to antidepressant treatment have been reported in those with decreased PCr levels.

Frontal lobe bioenergetic metabolism in depressed adolescents with bipolar disorder: a phosphorus-31 magnetic resonance spectroscopy study.

OBJECTIVES: To compare the concentrations of high-energy phosphorus metabolites associated with mitochondrial function in the frontal lobe of depressed adolescents with bipolar disorder (BD) and healthy controls (HC). METHODS: We used in vivo phosphorus-31 magnetic resonance spectroscopy ((31) P-MRS) at 3 Tesla to measure phosphocreatine (PCr), beta-nucleoside triphosphate (ß-NTP), inorganic phosphate (Pi), and other neurometabolites in the frontal lobe of eight unmedicated and six medicated adolescents with bipolar depression and 24 adolescent HCs. RESULTS: Analysis of covariance, including age as a covariate, revealed differences in PCr (p=0.037), Pi (p=0.017), and PCr/Pi (p=0.002) between participant groups. Percentage neurochemical differences were calculated with respect to mean metabolite concentrations in the HC group. Post-hoc Tukey-Kramer analysis showed that unmedicated BD participants had decreased Pi compared with both HC (17%; p=0.038) and medicated BD (24%; p=0.022). The unmedicated BD group had increased PCr compared with medicated BD (11%; p=0.032). The PCr/Pi ratio was increased in unmedicated BD compared with HC (24%; p=0.013) and with medicated BD (39%; p=0.002). No differences in ß-NTP or pH were observed. CONCLUSIONS: Our results support the view that frontal lobe mitochondrial function is altered in adolescent BD and may have implications for the use of Pi as a biomarker. These findings join volumetric studies of the amygdala, and proton MRS studies of n-acetyl aspartate in pointing to potential differences in neurobiology between pediatric and adult BD.