Atomoxetine in comorbid ADHD/PTSD: A randomized, placebo controlled, pilot, and feasibility study.

BACKGROUND: PTSD and ADHD often occur comorbidly. Research indicates that the cognitive deficits in PTSD may be related to the same disturbance of fronto-temporal systems as observed in ADHD, and ADHD has been shown to impact PTSD treatment outcomes. The presented study evaluated the safety and efficacy of atomoxetine in Veterans with comorbid ADHD/PTSD. METHODS: A double blind, randomized, placebo controlled, cross-over pilot and feasibility study was conducted. Atomoxetine was examined as an adjunctive treatment over this 10 weeks, two phase, crossover study which compared treatment with atomoxetine 80 mg daily to placebo daily. The primary outcome was improvement in ADHD symptoms as measured by the Conners' Adult ADHD Rating Scales-Self-Report: Short Version (CAARS-S:S), the Barkley Adult ADHD Rating Scale-IV (BAARS-IV), and the Adult ADHD Quality of Life-29 (AAQoL-29). Secondary outcomes included the Clinician Administered PTSD Scale (CAPS), Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36), and the response inhibition task Go/NoGo (GNG). RESULTS: Atomoxetine treated patients had greater reductions in ADHD symptoms as defined by total scores on the CAARS-S:S (F(1, 29) = 6.37, p = .017); both the BAARS-IV (F(1, 26) = 3.16, p = .087); and GNG overall errors test (F(1, 29) = 3.88, p = .06), reached a trend level of significance. No significant differences were noted in quality of life assessments, GNG latency periods, or CAPS scores. Atomoxetine was well-tolerated with no serious adverse events observed. CONCLUSIONS: In Veterans with ADHD comorbid with PTSD, atomoxetine demonstrated modest efficacy for ADHD symptoms; quality of life measures and PTSD symptoms were not affected.

Amitriptyline inhibits nonalcoholic steatohepatitis and atherosclerosis induced by high-fat diet and LPS through modulation of sphingolipid metabolism.

We reported previously that increased acid sphingomyelinase (ASMase)-catalyzed hydrolysis of sphingomyelin, which leads to increases in ceramide and sphingosine 1 phosphate (S1P), played a key role in the synergistic upregulation of proinflammatory cytokines by palmitic acid (PA), a major saturated fatty acid, and lipopolysaccharide (LPS) in macrophages. Since macrophages are vital players in nonalcoholic steatohepatitis (NASH) and atherosclerosis, we assessed the effect of ASMase inhibition on NASH and atherosclerosis cooperatively induced by high-PA-containing high-fat diet (HP-HFD) and LPS in LDL receptor-deficient (LDLR-/-) mice. LDLR-/- mice were fed HP-HFD, injected with low dose of LPS and treated with or without the ASMase inhibitor amitriptyline. The neutral sphingomyelinase inhibitor GW4869 was used as control. Metabolic study showed that both amitriptyline and GW4869 reduced glucose, lipids, and insulin resistance. Histological analysis and Oil Red O staining showed that amitriptyline robustly reduced hepatic steatosis while GW4869 had modest effects. Interestingly, immunohistochemical study showed that amitriptyline, but not GW4869, strongly reduced hepatic inflammation. Furthermore, results showed that both amitriptyline and GW4869 attenuated atherosclerosis. To elucidate the underlying mechanisms whereby amitriptyline inhibited both NASH and atherosclerosis, but GW4869 only inhibited atherosclerosis, we found that amitriptyline, but not GW4869, downregulated proinflammatory cytokines in macrophages. Finally, we found that inhibition of sphingosine 1 phosphate production is a potential mechanism whereby amitriptyline inhibited proinflammatory cytokines. Collectively, this study showed that amitriptyline inhibited NASH and atherosclerosis through modulation of sphingolipid metabolism in LDLR-/- mice, indicating that sphingolipid metabolism in macrophages plays a crucial role in the linkage of NASH and atherosclerosis.

Ziprasidone Augmentation of SSRI Antidepressants in Posttraumatic Stress Disorder: A Randomized, Placebo-Controlled Pilot Study of Augmentation Therapy.

BACKGROUND: Posttraumatic stress disorder (PTSD) is often a chronic, disabling illness for which antidepressant medications (ie, SSRI) are considered the primary psychopharmacological treatment. However, many patients remain refractory to antidepressants alone or in combination with psychotherapy. Safe and effective treatments for individuals with refractory PTSD are needed. This study aimed to examine ziprasidone augmentation of SSRI treatment of PTSD. METHODS: This was a 2-phase study. In phase 1, subjects were treated with paroxetine or sertraline for 8 weeks. Individuals refractory to the SSRI treatment then entered into phase II of the study and were randomized, in a double-blind fashion, to 8 weeks of treatment with either ziprasidone or placebo. The primary outcome measure was change in Clinician Administered PTSD Scale total scores with the intent-to-treat sample. Secondary outcome measures included Positive and Negative Syndrome Scale scores, measures of depression and anxiety, and safety measures. RESULTS: No significant differences were observed on the Clinician Administered PTSD Scale, Positive and Negative Syndrome Scale, or other outcome measures between ziprasidone and placebo groups. No significant differences were observed for safety measures including metabolic profiles, extrapyramidal symptoms/movement disorder rating scales, nor study dropout. CONCLUSIONS: Although no significant differences were noted in efficacy or safety measures between ziprasidone and placebo in this pilot study, the small sample size prevents definitive conclusions.

The relationship between combat-related posttraumatic stress disorder and the 5-HTTLPR/rs25531 polymorphism.

BACKGROUND: Empirical evidence suggests that there is a significant genetic influence in the development of posttraumatic stress disorder (PTSD). The serotonin transporter (5-HTT) gene (SLC6A4) has been identified as a prime candidate for the development of the disorder, as 5-HTT is a working target for selective serotonin reuptake inhibitors (SSRIs), first line treatment agents for PTSD. Several studies have reported associations between 5-HTT-linked promoter region (5-HTTLPR) polymorphism variants and increased rates of PTSD in civilian samples. This study investigated the role of the 5-HTTLPR polymorphism, triallelically classified, in a sample of combat veterans with and without PTSD. METHODS: Rates of PTSD were examined across three genotypes in a sample of 388 combat veterans. The short/long polymorphism of 5-HTTLPR and the A-G polymorphism within the 5-HTTLPR (rs25531) were genotyped, and statistical analyses were conducted. RESULTS: There were significant intergroup (PTSD versus non-PTSD) differences in the genotype frequencies of 5-HTTLPR/rs25531 (χ(2) [1, n = 388] = 16.23, P = 5.62 × 10(-5) ). The 5-HTTLPR S'/S' (low transcriptionally efficient) genotype was also associated with the PTSD severity score in the 228 participants who had combat severity data (r = .15, P = 0.03). CONCLUSIONS: The findings are consistent with previous research among civilian populations that have indicated that the low transcriptionally efficient S'/S' genotype of 5-HTTLPR is a risk factor for the development of PTSD after trauma exposure. Our findings are the first to examine this polymorphism and PTSD in a military sample. Additional large-scale investigations are needed to replicate these findings.

LPS and palmitic acid Co-upregulate microglia activation and neuroinflammatory response.

Growing evidence indicates that disturbances in the inflammatory response system can have deleterious effects on neuronal function and mental health. While the correlation between elevated peripheral inflammatory markers and psychiatric disorders are well documented, the exact molecular and neuronal mechanism underlying the connection between activated inflammation and neuropsychiatric behaviour remain elusive. Microglia activation is the key interface between neuro-inflammation and manifestation of psychiatric symptoms. Microglia are immunocompetent cells in the central nervous system (CNS) which are primarily involved in the response to inflammatory stimulation and are widely used to study neuroinflammation and test anti-inflammatory chemicals. In the brain, activated microglia play very important roles during neuroinflammation and neurodegeneration. Both stress-related disorders such as Depression and PTSD, and medical conditions such as metabolic syndrome (Mets) and type 2 diabetes (TD2) are associated with increased levels of both saturated fatty acids (SFAs) and lipopolysaccharide (LPS) in circulation. This work was aimed at determining whether SFA interacts with LPS to activate microglia, thus up-regulating neuroinflammatory processes and, if so which pathways were involved in this process. Our results showed that low-dose LPS and palmitic acid (PA) robustly stimulated the expression of proinflammatory cytokines, and the combination of PA and LPS further upregulated proinflammatory cytokines through MAPK, NFκB and AP-1 signaling pathways in the HMC3-human microglial cell line. In addition, PA stimulated ceramide production via de novo synthesis and sphingomyelin hydrolysis, and the combination of LPS and PA further increased ceramide production. HMC3 co-cultured with macrophage and lymphocyte enhanced LPS and PA induced-inflammatory response more than that in HMC3 alone. These results indicate that LPS interacts with PA to activated microglia; induced neuroinflammatory responses, upregulate proinflammatory cytokine expression via MAPK, NFκB, and AP-1 signaling pathways, and induced sphingolipid metabolism in HMC3. These observations suggest that inhibiting microglia activation and reducing LPS and PA-induced inflammatory response may be useful in the treatment of neuronal inflammatory diseases.

Dopamine transporter (DAT1) gene in combat veterans with PTSD: A case-control study.

The dopamine transporter (DAT1) gene has been postulated to be involved in PTSD; however, existing studies have shown inconsistencies when examining genotypic and allelic associations. The primary objective of this study was to examine whether DAT1-40bp-VNTR (DAT1) 9R polymorphism might increase the risk of PTSD development in combat veterans, utilizing a case-control gene association study with both control and PTSD cases having previous exposure to combat traumas. Participants with PTSD (N = 365) and combat-exposed controls without PTSD (N = 298) were included in analysis. After controlling for race, sex and age, when dichotomized, absence of DAT1 10R/10R genotypes was associated with PTSD diagnosis compared to no PTSD diagnosis; these results were not statistically significant when trichotomized 10R/10R, 10R/X, 9R/9R. Similarly, odds ratio for absence of 10R/10R genotype showed a statistically significant increase in the risk of developing PTSD. DAT1 genotype was also associated with statistically significant mean total CAPS scores, both when dichotomized and trichotomized. In conclusion, our results indicate that the absence of 10R/10R is associated with an increased risk of PTSD and higher CAPS total scores.

The Effects of Inattentiveness and Hyperactivity on Posttraumatic Stress Symptoms: Does a Diagnosis of Posttraumatic Stress Disorder Matter?

Objective: To address the nature of associations between ADHD symptoms and posttraumatic stress disorder (PTSD) psychopathology in adult military veterans. Method: Ninety-five combat veterans, with PTSD (n = 63) and without PTSD (n = 32), were recruited for this study. PTSD was assessed with the Clinician-Administered PTSD Scale (CAPS) and ADHD was assessed with Connors' Adult ADHD Rating Scale-Self-Report: Short Version (CAARS-S:S). Results: PTSD participants endorsed greater hyperactivity or restlessness, inattention or memory problems, and impulsivity or emotional lability scores than participants without PTSD. Among PTSD participants, inattention or memory problems and impulsivity or emotional lability were significant predictors of total PTSD symptoms, but only inattention or memory problems significantly predicted PTSD symptoms when other ADHD symptom clusters were considered simultaneously. Conclusion: Our data suggest that inattention may serve as a risk factor for posttraumatic stress symptoms following combat exposure.

Reduced Expression of Immune Mediators by T-Cell Subpopulations of Combat-Exposed Veterans With Post-Traumatic Stress Disorder.

Post-traumatic stress disorder (PTSD) has been suggested to be associated with an inflammatory immune state, although few studies have examined peripheral blood lymphocytes in subjects that have PTSD and compared immune parameters to subjects that experienced similar trauma, but did not develop PTSD. An exploratory approach was undertaken to compare phenotypes of blood CD4+ and CD8+ subpopulations and their expression of immune mediators between Veterans of the Iraq and Afghanistan wars who experienced similar levels of combat, with some developing PTSD and other not. The results of this study did not demonstrate evidence of enhanced immune activation of peripheral blood lymphocytes. Instead, the results showed a decline in expression of the pro-inflammatory mediator IFN-γ and the cytotoxin granzyme B in CD8+ subpopulations from Veterans with PTSD. While the reductions in expression of IFN-γ and granzyme B did not reach statistical significance when examining the CD8+ cell population as a whole, the declines were significant when examining the CD8+ cell subpopulations, with different mediators being reduced in different subpopulations. The most prominent decline in IFN-γ expression was by the unconventional CD8dimCD3+ T-cell subpopulation that has been associated with chronic infection and immune fatigue. The decline in granzyme B was most prominent in the NK-containing CD8dimCD3- subpopulation of Tcells. Consequently, analysis of blood leukocyte subpopulations, rather than bulk lymphocyte groups, reveals a dampened level of immune reactivity in combat-exposed Veterans with PTSD compared to combat-exposed Veterans without PTSD.

Atomoxetine treatment of ADHD in Tourette syndrome: reduction in motor cortex inhibition correlates with clinical improvement.

OBJECTIVE: In children with attention deficit hyperactivity disorder (ADHD), clinical responses to the selective norepinephrine reuptake inhibitor atomoxetine (ATX) vary. We sought to determine in children with Tourette Syndrome (TS) whether clinical responses correlate with changes in short interval cortical inhibition (SICI). METHODS: Fourteen children, ages 8-16, with ADHD and TS were treated open-label with ATX for one month. ADHD rating scale scores and SICI, measured with paired-pulse transcranial magnetic stimulation (pTMS), were assessed blindly and independently at treatment onset and one month later. RESULTS: Eleven children, mean ADHD rating scale scores 31.8 (SD 8.2) at onset, completed the study. After one month, ADHDRS changes ranged from an increase of 4 points to a decrease (improvement) of 24 points (mean change -9.6, SD 9.1). The changes in ADHDRS scores correlated with reduction in SICI (r=.74, p=.010). CONCLUSIONS: In children with TS, one month of atomoxetine treatment appears to induce correlated improvements in ADHD and, paradoxically, further reductions in cortical inhibition. SIGNIFICANCE: PTMS-evoked SICI in ADHD with TS may be a biomarker of both deficiency and compensatory changes within cortical interneuronal systems. Effective atomoxetine treatment may augment compensatory processes and thereby reduce SICI.

Dopamine transporter genotype influences the physiological response to medication in ADHD.

Attention deficit hyperactivity disorder (ADHD) is a complex, multifactorial disorder characterized by physical hyperactivity and behavioural disinhibition. Short interval cortical inhibition (SICI), measured in motor cortex with transcranial magnetic stimulation, is reduced in ADHD and correlates with symptom severity. However, ADHD medication-induced changes in SICI vary widely among normal individuals and have not been well studied in children with ADHD. Therefore, we undertook this study to measure and compare effects of two ADHD medications, methylphenidate (MPH), a psychostimulant, and atomoxetine (ATX), a selective norepinephrine reuptake inhibitor, on SICI in children with ADHD. In addition, we wished to determine whether a genetic variation in the dopamine transporter (DAT1), a site of action of MPH, could influence the effects of MPH or ATX on SICI. We performed a randomized, double-blind, single-dose, crossover study comparing 0.5 mg/kg MPH with 1.0 mg/kg ATX in 16 children with ADHD, aged 8-17. Seven were homozygotes and 9 heterozygotes for the DAT1 variable number of tandem repeats 10-repeat allele. Medication and genotype effects on SICI were estimated with repeated measures, mixed model regression. We found that MPH and ATX had similar effects on SICI. However, medication effects differed significantly by DAT1 genotype [F(2,13) = 13.04, P = 0.0008]. Both MPH and ATX increased SICI in heterozygotes but not in 10-repeat homozygotes. In conclusion, MPH and ATX have similar effects on SICI in children with ADHD. A genetic variation in DAT1, previously linked to ADHD risk and MPH behavioural responses, influences the neurophysiological effects of both MPH and ATX.

Posttraumatic Stress Disorder: An Immunological Disorder?

Patients with posttraumatic stress disorder (PTSD) exhibit an increased state of inflammation. Various animal models for PTSD have shown some of the same immune imbalances as have been shown in human subjects with PTSD, and some of these studies are discussed in this review. However, animal studies can only indirectly implicate immune involvement in PTSD in humans. This review of mainly studies with human subjects focuses on dissecting the immunological role in the pathogenesis of PTSD following initial trauma exposure. It addresses both the inflammatory state associated with PTSD and the immune imbalance between stimulatory and inhibitory immune mediators, as well as variables that can lead to discrepancies between analyses. The concept of immunological treatment approaches is proposed for PTSD, as new treatments are needed for this devastating disorder that is affecting unprecedented numbers of Veterans from the long-standing wars in the Middle East and which affects civilians following severe trauma.

Cue-dependent inhibition in posttraumatic stress disorder and attention-deficit/hyperactivity disorder.

OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) and posttraumatic stress disorder (PTSD) are common among military veterans, but the comorbidity of these two psychiatric disorders remains largely unstudied. Evaluating response inhibition and cue-dependent learning as behavioral and neurocognitive mechanisms underlying ADHD/PTSD can inform etiological models and development of tailored interventions. METHOD: A cued go/no-go task evaluated response inhibition in 160 adult males. Participants were recruited from the community and a Veterans Administration medical center. Four diagnostic groups were identified: ADHD-only, PTSD-only, ADHD+PTSD, controls. RESULTS: Group differences were observed across most indices of inhibitory functioning, reaction time, and reaction time variability, whereby PTSD-only and ADHD+PTSD participants demonstrated deficits relative to controls. No cue dependency effects were observed. CONCLUSION: Finding complement prior work on neurocognitive mechanisms underlying ADHD, PTSD, and ADHD+PTSD. Lack of expected group differences for the ADHD-only group may be due to limited power. Additional work is needed to better characterize distinctions among clinical groups, as well as to test effects among women and youth.

Relationships between GAT1 and PTSD, Depression, and Substance Use Disorder.

Post-traumatic stress disorder (PTSD), Major Depressive Disorder (MDD), and Substance Use Disorder (SUD) have large public health impacts. Therefore, researchers have attempted to identify those at greatest risk for these phenotypes. PTSD, MDD, and SUD are in part genetically influenced. Additionally, genes in the glutamate and gamma-aminobutyric acid (GABA) system are implicated in the encoding of emotional and fear memories, and thus may impact these phenotypes. The current study examined the associations of single nucleotide polymorphisms in GAT1 individually, and at the gene level, using a principal components (PC) approach, with PTSD, PTSD comorbid with MDD, and PTSD comorbid with SUD in 486 combat-exposed veterans.  Findings indicate that several GAT1 SNPs, as well as one of the GAT1 PCs, was associated with PTSD, with and without MDD and SUD comorbidity. The present study findings provide initial insights into one pathway by which shared genetic risk influences PTSD-MDD and PTSD-SUD comorbidities, and thus identify a high-risk group (based on genotype) on whom prevention and intervention efforts should be focused.

PTSD, a Disorder with an Immunological Component.

Post-traumatic stress disorder (PTSD) has been associated with an inflammatory state. However, few studies have addressed the mechanisms underlying this immune imbalance that favors inflammation or how this imbalance contributes to PTSD. Whether the immune imbalance influences responsiveness or unresponsiveness of patients to PTSD treatments is currently not known. This review brings forward an immune emphasis to a mental health disorder that is unprecedented in its prevalence among combat Veterans of the ongoing conflicts in Iraq and Afghanistan and which also afflicts civilians who have undergone extreme traumatic experiences, such as following natural disasters, serious accidents, or assaults. Included is an overview of the correlative associations in human subjects between PTSD and inflammation and studies in animal models of PTSD, demonstrating causal contributions of inflammation and immune dysregulation to PTSD-like behavior following stress exposure.

An exploratory approach demonstrating immune skewing and a loss of coordination among cytokines in plasma and saliva of Veterans with combat-related PTSD.

Studies have suggested PTSD to be associated with an inflammatory state, although few studies have examined the balances between stimulatory and inhibitory immune mediators in PTSD. An exploratory approach was taken to assess the immune imbalances between Th1 stimulatory, inflammatory and inhibitory mediators associated with PTSD. This approach focused on a tightly-controlled and relatively homogeneous population of Veterans, all with similar levels of combat exposure in the Afghanistan and Iraq wars, but some testing negative and others testing positive for PTSD. Although the sample size was small (6 controls and 7 with PTSD) and a limitation of this study, the results showed significant imbalances in immune cytokines favoring a Th1 and inflammatory state, with reduced levels of inhibitory cytokines in Veterans with PTSD. This was particularly prominent in the saliva of PTSD subjects compared to in their plasma.

Exploring the association between a cholecystokinin promoter polymorphism (rs1799923) and posttraumatic stress disorder in combat veterans.

BACKGROUND: Cholecystokinin (CCK) is a neuropeptide that has been implicated in understanding the acquisition and extinction of fear. Research on CCK in anxiety has primarily focused on understanding panic attacks and panic disorder. Emerging data suggests that CCK may also hold promise in understanding the development and maintenance of posttraumatic stress disorder (PTSD). METHOD: The present study examined whether a single nucleotide polymorphism in the promoter region of the CCK gene (C>T; rs1799923) was associated with an increased prevalence of PTSD as well as with severity of PTSD symptoms among a sample of 457 combat veterans. RESULTS: Results demonstrated that participants with either the heterozygous or homozygous T allele had an increased prevalence of PTSD relative to participants with the CC genotype (OR=2.17; 95% CI [1.37-3.43]). LIMITATIONS: The relatively small sample size precluded examination of racial/ethnic differences. Findings were also limited by the absence of a systematic assessment of comorbid anxiety psychopathology. CONCLUSIONS: These data offer preliminary evidence supporting an association between the rs1799923 polymorphism in the CCK gene and PTSD. Additional research is needed to better understand the nature of this relationship.

Possible association of a cholecystokinin promoter variant to schizophrenia.

Several lines of research indicate a cholecystokinin (CCK) deficit in schizophrenia patients. A C to T substitution was found in the promoter region of the CCK gene. We investigated this promoter variant in patients with schizophrenia and geographically-matchedcontrols. The T allele was detected in 24% of the 85 schizophrenics and 16% of the 247 controls. No significant difference in the T allele frequency was found between patients and controls (chi(2) = 2.77, P > 0.1). The schizophrenia sample was analyzed further along the dimensions of positive and negative symptoms. The patients with prominent negative symptoms presented a statistically significant association to the T allele (chi(2) = 4.13, P < 0.04). However, the significance disappeared after the Bonferroni correction (P > 0.15). Since the case-control analysis may present incorrect ethnic match between cases and controls, we applied the family-based tests to verify the above findings. Both transmission disequilibrium test (TDT; chi(2) = 5.33, P < 0.025 in 12 trios) and haplotype relative risk (HRR; chi(2) = 3.844, P < 0.05 in 60 trios) indicated a significantly high transmission of T allele to schizophrenia offspring probands from their parents. While our family-based tests seem to support the CCK involvement in schizophrenia, no definite conclusion can be drawn based on such a small sample size. This preliminary finding is subjected to future investigations.

Variation in SLC1A1 is related to combat-related posttraumatic stress disorder.

Candidate gene studies have yet to investigate the glutamate system, the primary excitatory neurotransmitter of the HPA-axis related to PTSD risk. We investigated 13 SNPs in the glutamate transporter gene (SLC1A1) in relation to PTSD among combat-exposed veterans. Participants (n=418) completed a diagnostic interview and provided a blood sample for DNA isolation and genotyping. A subset of participants (n=391) had severity and combat exposure data available. In the primary logistic regression gender and rs10739062 were significant predictors of PTSD diagnosis (OR=0.50; OR=1.43). In the linear regression analysis, combat exposure was the only significant predictor (ß=0.16) of severity. A computed genetic risk sum score was significant in relation to PTSD diagnosis (OR=1.15) and severity scores (ß=0.14) above and beyond the effects of combat exposure. This study provides preliminary support for the relationship of glutamate transporter polymorphisms to PTSD risk and the need for further genetic studies within this system.