Decreased Cerebrospinal Fluid Allopregnanolone Levels in Women with Posttraumatic Stress Disorder

Rasmusson, Ann M.; Pinna, Graziano; Paliwal, Prashni; Weisman, David; Gottschalk, Christopher; Charney, Dennis S.; Krystal, John H.; Guidotti, Alessandro

doi:10.1016/j.biopsych.2006.03.026

Cited by 248 publications

(234 citation statements)

References 95 publications

Supporting

Mentioning

222

Contrasting

Unclassified

Order By: Relevance

“…The CSF ALLO levels in these subjects increased significantly after SSRI treatment, and the increase in ALLO was significantly correlated with improvement in depressive symptoms (Uzunova et al, 1998). In women with PTSD, CSF ALLO levels were reduced by 60% compared with healthy controls, with significant negative correlations between the ALLO/DHEA ratio and PTSD and negative mood symptoms (Rasmusson et al, 2006). Subjects with PTSD were found to have normal levels of the allopregnanolone precursor, 5α-dihydroprogesterone, but a high 5α-dihydroprogesterone/ ALLO ratio, suggesting that the decrease in ALLO was either due to a decrease in 3α-HSD expression or activity or increased metabolism of ALLO.…”

Section: Discussionmentioning

confidence: 89%

“…Further studies are warranted to further explore this hypothesis. Whether relative allopregnanolone deficiency is implicated in the pathophysiology of several psychiatric conditions, including depression (Romeo et al, 1998;Schule et al, 2007;Strohle et al, 1999;Uzunova et al, 1998), anxiety (Schule et al, 2014), and PTSD (Rasmusson et al, 2006), is an active area of investigation that has been limited by the lack of availability, high cost and time-consuming nature of GC-MS measurements. A small number of both cross-sectional and prospective treatment studies have examined allopregnanolone levels by GC-MS in the serum and CSF of subjects with MDD and PTSD, but no previous studies have explored the role of neuroactive steroids by GC-MS in women with AN or OW/OB.…”

Section: Discussionmentioning

confidence: 99%

“…Although less potent than allopregnanolone, 3α-androstanediol is also a positive modulator of GABA A receptor action (Reddy, 2004). Increases in GABA A receptor activity dampen neuronal excitation and result in anxiolytic, antidepressant, and sedative effects in humans (Eser et al, 2006a;Eser et al, 2006b;Rasmusson et al, 2006;Rupprecht and Holsboer, 1999a,b,;Sigel and Steinmann, 2012). However, little is known about whether such GABAergic neuroactive steroids contribute to the etiopathology of affective disorders in women at the extremes of the weight spectrum, which are enriched for both depression and anxiety symptoms.…”

Section: Introductionmentioning

confidence: 99%

“…Small studies have suggested that both cerebrospinal fluid (CSF) and serum allopregnanolone levels may be low in patients with major depressive disorder (MDD) and posttraumatic stress disorder (PTSD) as compared with healthy controls (Rasmusson et al, 2006;Romeo et al, 1998;Strohle et al, 1999;Uzunova et al, 1998). Girdler et al (2012) additionally noted decreased conversion of progesterone to allopregnanolone in women with a history of depression.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Neuroactive Steroids and Affective Symptoms in Women Across the Weight Spectrum

Dichtel

Lawson

Schorr

et al. 2017

Neuropsychopharmacol.

Self Cite

View full text Add to dashboard Cite

3α-5α-Tetrahydroprogesterone, a progesterone metabolite also known as allopregnanolone, and 5α-androstane-3α,17β-diol, a testosterone metabolite also known as 3α-androstanediol, are neuroactive steroids and positive GABA A receptor allosteric modulators. Both anorexia nervosa (AN) and obesity are complicated by affective comorbidities and hypothalamic-pituitary-gonadal dysregulation. However, it is not known whether neuroactive steroid levels are abnormal at the extremes of the weight spectrum. We hypothesized that serum allopregnanolone and 3α-androstanediol levels would be decreased in AN compared with healthy controls (HC) and negatively associated with affective symptoms throughout the weight spectrum, independent of body mass index (BMI). Thirty-six women were 1 : 1 age-matched across three groups: AN, HC, and overweight/obese (OW/OB). AN were amenorrheic; HC and OW/OB were studied in the follicular phase. Fasting serum neuroactive steroids were measured by gas chromatography/mass spectrometry. Mean Hamilton depression and anxiety scores were highest in AN (po0.0001). Mean serum allopregnanolone was lower in AN and OW/OB than HC (AN 95.3 ± 56.4 vs OW/OB 73.8 ± 31.3 vs HC 199.5 ± 167.8 pg/ml, p = 0.01), despite comparable mean serum progesterone. Allopregnanolone levels, but not progesterone levels, were negatively associated with depression and anxiety symptom severity, independent of BMI. Serum 3α-androstanediol levels did not differ among groups and were not associated with depression or anxiety scores, despite a significant negative association between free testosterone levels and both anxiety and depression severity. In conclusion, women at both extremes of the weight spectrum have low mean serum allopregnanolone, which is associated with increased depression and anxiety severity, independent of BMI. Neuroactive steroids such as allopregnanolone may be potential therapeutic targets for depression and anxiety in traditionally treatment-resistant groups, including AN.

show abstract

Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Neuroactive Steroids and Affective Symptoms in Women Across the Weight Spectrum

Dichtel

Lawson

Schorr

et al. 2017

Neuropsychopharmacol.

Self Cite

View full text Add to dashboard Cite

show abstract

“…Both 3a,5a-THP and 3a,5a-THDOC enhance neuronal inhibition at binding sites on GABA A receptors (Hosie et al, 2006) and produce behavioral effects similar to those of ethanol. These GABAergic steroids are potent positive modulators of GABA A receptors, producing pharmacological effects in nanomolar concentrations (Morrow et al, 1987), and studies suggest that modulating GABAergic steroid levels may have therapeutic value for treating multiple psychiatric disorders (Marx et al, 2006;Morrow, 2007;Rasmusson et al, 2006;Strohle et al, 2002;Uzunova et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Ethanol Alters Local Cellular Levels of (3α,5α)-3-Hydroxypregnan-20-one (3α,5α-THP) Independent of the Adrenals in Subcortical Brain Regions

Cook

Nelli

Neighbors

et al. 2014

Neuropsychopharmacol

View full text Add to dashboard Cite

The neuroactive steroid (3a,5a)-3-hydroxypregnan-20-one (3a,5a-THP or allopregnanolone) is a positive modulator of GABA A receptors synthesized in the brain, adrenal glands, and gonads. In rats, ethanol activates the hypothalamic-pituitary-adrenal axis and elevates 3a,5a-THP in plasma, cerebral cortex, and hippocampus. In vivo, these effects are dependent on both the pituitary and adrenal glands. In vitro, however, ethanol locally increases 3a,5a-THP in hippocampal slices, in the absence of adrenal influence. Therefore, it is not known whether ethanol can change local brain levels of 3a,5a-THP in vivo, independent of the adrenals. To directly address this controversy, we administered ethanol (2 g/kg) or saline to rats that underwent adrenalectomy (ADX) or received sham surgery and performed immunohistochemistry for 3a,5a-THP. In the medial prefrontal cortex (mPFC), ethanol increased 3a,5a-THP after sham surgery, compared with saline controls, with no ethanol-induced change in 3a,5a-THP following ADX. In subcortical regions, 3a,5a-THP was increased independent of adrenals in the CA1 pyramidal cell layer, dentate gyrus polymorphic layer, bed nucleus of the stria terminalis, and paraventricular nucleus of the hypothalamus. Furthermore, ethanol decreased 3a,5a-THP labeling in the nucleus accumbens shore and central nucleus of the amygdala, independent of the adrenal glands. These data indicate that ethanol dynamically regulates local 3a,5a-THP levels in several subcortical regions; however, the adrenal glands contribute to 3a,5a-THP elevations in the mPFC. Using double immunofluorescent labeling we determined that adrenal dependence of 3a,5a-THP induction by ethanol is not due to a lack of colocalization of 3a,5a-THP with the cholesterol transporters steroidogenic acute regulatory protein (StAR) or translocator protein (TSPO).

show abstract