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GME Research Review

GME Research Review is a monthly newsletter where internationally recognized experts select, summarize, and provide a clinical commentary on the latest published research in psychiatry. Each summary has been derived from the relevant article’s abstract and the clinical commentary has been provided by our expert.


ISSUE 19, October 2013 — Guest Commentator: Allan H. Young, FRCPsych, Institute of Psychiatry, KCL, London

Bipolar Disorder is Associated with the rs6971 Polymorphism in the Gene Encoding 18kDa Translocator Protein (TSPO)          

Colasanti A, Owen DR, Grozeva D, et al      
Psychoneuroendocrinology. 2013. Aug 10. [Epub ahead of print]    

Objective: To assess whether bipolar disorder (BD) is associated with the rs6971 polymorphism and the gene encoding the 18kDa translocator protein (TSPO).

Methods: This large-scale, case-control study aimed to test the association between the SNP rs6971 and BD.

  • The study utilized 1,868 cases reported in the BD subset of the Wellcome Trust Case-Control Consortium (WTCCC) genome-wide association study (GWAS) as well as 2,938 controls.
  • The analysis of the association between rs6971 and diagnosis of BD was also examined using the meta-analytic data of the Psychiatric Genome-Wide Association Study Consortium Bipolar Disorder group (PGC-BD), which combines primary genotype data from large GWAS datasets.
  • The PGC-BD dataset is made up of 7,481 cases and 9,250 controls, and also includes the WTCCC data.

The authors report a nominal association between this TSPO polymorphism and the diagnosis of BD in both the genome-wide dataset of the WTCCC and the PCG-BD (OR=1.11, P=.007; OR=1.10, P=.011, respectively).

Conclusions: These data indicate a nominal association between the rs6971 SNP in the TSPO gene and the diagnosis of BD.

Clinical Commentary          
TSPO-mediated transport of cholesterol into the mitochondrion is a necessary step in steroid synthesis. The rs6971 polymorphism in the TSPO gene causes an amino acid substitution (Ala147Thr) within the transmembrane domain where the cholesterol-binding pocket is located, and has been shown to affect the steroidogenic pathway. Although the pathophysiological processes involved in BD remain unclear, previous work has shown abnormalities in hypothalamic-pituitary-adrenal (HPA) regulation. This amino acid substitution affects HPA regulation and hence may potentially predispose to bipolar disorder. This also supports the notion that HPA dysregulation has a causal role in bipolar disorder and is not just a consequence of the disease.



A Randomized Trial to Examine the Effect of Mifepristone on Neuropsychological Performance and Mood in Patients with Bipolar Depression             

Watson S, Gallagher P, Porter RJ, et al.           
Biol Psychiatry. 2012;72(11):943-949.

To examine the effect of mifepristone on neuropsychological performance and mood in patients with bipolar depression.

Methods: These authors examined the longer-term efficacy of oral mifepristone 600 mg/day as an adjunctive treatment.

  • This was a 1-week, placebo-controlled, randomized, double-blind trial in 60 patients with bipolar depression.
  • The primary outcome measure was performance on a spatial working memory (SWM) task.
  • A comparator group of healthy control subjects was also recruited.

At baseline, neuropsychological performance of patients was impaired, but hypothalamic-pituitary-adrenal axis function did not differ from that of control subjects. Mifepristone treatment was associated with a time-limited increase in cortisol awakening response and with a sustained improvement in SWM performance, which was evident 7 weeks after the cessation of treatment. The magnitude of this neuropsychological response was predicted by the magnitude of the cortisol response to mifepristone. The response occurred in the absence of a significant improvement in depressed mood.

Conclusions:  These data accord with the findings of a previous study and demonstrate that brief treatment with mifepristone is associated with a sustained improvement in SWM, an effect that might be mediated by a persistent enhancement in hippocampal mineralocorticoid receptor function.

Clinical Commentary          
Deficits in neuropsychological performance are commonly found in patients with bipolar disorder and represent a potential treatment target for novel therapeutic strategies. This group previously demonstrated a beneficial effect on spatial working memory (SWM) of treatment for 1 week with the progesterone and glucocorticoid receptor antagonist mifepristone. Results were evident 2 weeks after the cessation of treatment. These data confirm the initial findings and strengthen the case for larger, more definitive studies.



Lithium in the Public Water Supply and Suicide Mortality in Texas      

Blüml V, Regier MD, Hlavin G et al.            
J Psychiatr Res. 2013;47(3):407-411.

Objective: To evaluate the association between lithium levels in the public water supply and county-based suicide rates in Texas.

Methods: A state-wide sample of 3,123 lithium measurements in the public water supply was examined relative to suicide rates in 226 Texas counties. Linear and Poisson regression models were adjusted for socioeconomic factors in estimating the association.

Results: Lithium levels in the public water supply were negatively associated with suicide rates in most statistical analyses.

Conclusions: These data provide confirmatory evidence that higher lithium levels in the public drinking water are associated with lower suicide rates. This association needs clarification through examination of possible neurobiological effects of low natural lithium doses.

Clinical Commentary          
There is increasing evidence from ecological studies that lithium levels in drinking water are inversely associated with suicide mortality and this effect is biologically plausible. Previous studies of this association were criticized for using inadequate statistical methods and neglecting socioeconomic confounders. However, the evidence is mounting that environmental levels of lithium may have important effects on the brain and related disorders.  Environmental lithium is an intriguing area for future research.



Extended-Release Quetiapine Fumarate (Quetiapine XR) Monotherapy and Quetiapine XR or Lithium as Add-on to Antidepressants in Patients with Treatment-Resistant Major Depressive Disorder

Bauer M, Dell’osso L, Kasper S, et al.
J Affect Disord. 2013;151(1):209-219.

To examine the effects the effects of quetiapine XR monotherapy and quetiapine XR or lithium as add-on to antidepressants in patients with treatment-resistant major depressive disorder. 


  • This was a 6-week, randomized, open-label, rater-blinded trial.
  • The study compared lithium (0.6-1.2 mmol/L) and once-daily extended-release quetiapine fumarate (quetiapine XR) 300 mg/day as adjunctive treatments to antidepressant and quetiapine XR monotherapy in patients with treatment-resistant MDD.
  • Primary efficacy measure: change in Montgomery Åsberg Depression Rating Scale (MADRS) total score from randomization to week 6 with a pre-specified non-inferiority limit of 3 points on the MADRS.

At week 6, both add-on quetiapine XR (n=231) and quetiapine XR monotherapy (n=228) were non-inferior to add-on lithium (n=229). LSM MADRS total score change was numerically greater at day 4 for both quetiapine XR groups (add-on and monotherapy; P<.01) compared with add-on lithium. At week 6, the differences between groups for the secondary endpoints of MADRS response (≥50% reduction in total score), MADRS remission (total score ≤10, add-on quetiapine XR only), and Clinical Global Impressions ('much'/'very much' improved) were numerically similar. Overall tolerability was consistent with the known profiles of both treatments. Limitations of this study included the open-label study design (although MADRS and laboratory measurements were performed by treatment-blinded raters) and relatively short study duration with no assessments in the continuation phase.

Conclusions: Add-on quetiapine XR (300 mg/day) and quetiapine XR monotherapy (300 mg/day) are non-inferior to add-on lithium in the management of patients with treatment-resistant MDD.

Clinical Commentary
Patients with treatment-resistant major depressive disorder (MDD) remain a common clinical challenge and previous studies have shown modest benefits from commonly employed pharmacotherapeutic strategies.  These data suggest that quetiapine XR may be helpful in this patient group.



Hypomania Spectrum Disorders From Adolescence to Adulthood: a 15-Year Follow-up of a Community Sample 

Päären A, von Knorring AL, Olsson G, et al.
J Affect Disord. 2013;145(2):190-199.

To examine the longitudinal course of hypomania spectrum disorders from adolescence to adulthood.


  • A community sample of adolescents (N=2,300) was screened for depressive symptoms.
  • Adolescents (16–17 years) with a positive screening and matched controls were interviewed with a structured diagnostic interview.
  • A blinded follow-up assessment was conducted 15 years later; with a structured diagnostic interview covering the age span 19–31 years.
  • Questions about treatment and family history were included.

Ninety adolescents 16–17 years with a lifetime hypomania spectrum episode (3.9% of the total sample) were identified. The hypomania symptoms reported by the full syndromal and the brief-episode groups were similar, whereas the subsyndromal group per definition reported fewer symptoms. Very few patients suffered mania in adulthood compared to major depression in adulthood (Table). Incidence of mood episodes in adulthood did not differ between the subgroups of hypomania spectrum. A limitation of the study was that 29% of the participants with hypomania spectrum were lost to follow-up.

Course of Illness

N (%)

Hypomania Spectrum Episode

  -  Full syndromal

 -   Brief-episode (<4 days)

  - Subsyndromal (1–2 main symptoms; 1–2 
     additional symptoms)





Follow-up interview

64 (71%)

Major depression in adulthood

38 (59%)

Mania in adulthood

2 (3%)

Hypomania in adulthood

4 (6%)

Conclusion:  The results indicate that only a small proportion of adolescents with hypomania spectrum episodes continue to have (hypo)mania in adulthood. Thus, maintenance or prophylactic treatment does not seem warranted for this group.

Clinical Commentary          
There is a lack of scientific knowledge about the broader spectrum of hypomania in adolescence and the course over time, which this study addressed. These longitudinal data, spanning from adolescence to age 31 years, suggest caution is warranted with regards to on-going treatment.


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