Sex Differences in Antidepressant Response in Recent Antidepressant Clinical Trials

Khan, Arif; Brodhead, Amy E.; Schwartz, Kelly A.; Kolts, Russell L.; Brown, Walter A.

doi:10.1097/01.jcp.0000168879.03169.ce

Cited by 215 publications

(145 citation statements)

References 22 publications

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“…Of the published peer-reviewed studies, five found no difference in the efficacy of SSRIs in men and women (25)(26)(27)(28)(29), and six found SSRIs to be more effective in women (30)(31)(32)(33)(34)(35). There are no reports of SSRIs being more effective in men.…”

Section: Significancementioning

confidence: 92%

Serotonin and arginine–vasopressin mediate sex differences in the regulation of dominance and aggression by the social brain

Terranova

Song

Larkin

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

102

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There are profound sex differences in the incidence of many psychiatric disorders. Although these disorders are frequently linked to social stress and to deficits in social engagement, little is known about sex differences in the neural mechanisms that underlie these phenomena. Phenotypes characterized by dominance, competitive aggression, and active coping strategies appear to be more resilient to psychiatric disorders such as posttraumatic stress disorder (PTSD) compared with those characterized by subordinate status and the lack of aggressiveness. Here, we report that serotonin (5-HT) and arginine-vasopressin (AVP) act in opposite ways in the hypothalamus to regulate dominance and aggression in females and males. Hypothalamic injection of a 5-HT1a agonist stimulated aggression in female hamsters and inhibited aggression in males, whereas injection of AVP inhibited aggression in females and stimulated aggression in males. Striking sex differences were also identified in the neural mechanisms regulating dominance. Acquisition of dominance was associated with activation of 5-HT neurons within the dorsal raphe in females and activation of hypothalamic AVP neurons in males. These data strongly indicate that there are fundamental sex differences in the neural regulation of dominance and aggression. Further, because systemically administered fluoxetine increased aggression in females and substantially reduced aggression in males, there may be substantial gender differences in the clinical efficacy of commonly prescribed 5-HT-active drugs such as selective 5-HT reuptake inhibitors. These data suggest that the treatment of psychiatric disorders such as PTSD may be more effective with the use of 5-HT-targeted drugs in females and AVP-targeted drugs in males.hamster | gender differences | agonistic | social behavior | fluoxetine P rominent sex differences occur in the incidence, development, and clinical course of many psychiatric disorders. Women, for example, have higher rates of depression and anxiety disorders such as posttraumatic stress disorder (PTSD), whereas men more frequently suffer from autism and attention deficit disorders (1-4). Because little is known about sex differences in the efficacy of treatments for these disorders, current treatment strategies are largely the same for both sexes. The development of effective treatments for both women and men can proceed with a clear understanding of sex differences in the mechanisms and etiology of psychiatric disorders. Many of these disorders are linked to deficits in adaptive social skills (5, 6); therefore, understanding the neural mechanisms underlying social engagement in both sexes is essential. In most mammalian species, social interactions among both sexes are governed by dominance relationships. As such, behaviors associated with these relationships (e.g., social recognition, stress, competitive aggression) are the foundation for social interactions and are highly relevant for understanding psychiatric disorders (7-9). Emerging genetic and environmental...

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Section: Significancementioning

confidence: 92%

Serotonin and arginine–vasopressin mediate sex differences in the regulation of dominance and aggression by the social brain

Terranova

Song

Larkin

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

102

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“…Together, these observations suggest the potential importance of considering the role of sex and the ovarian steroid milieu in evaluating the efficacy of antidepressant therapy. Indeed, several studies have reported that women respond better to selective 5-HT re-uptake inhibitors (SSRI) than men (Kornstein et al, 2000;Joyce et al, 2003;Khan et al, 2005). Animal models of depression are usually based on the reproduction of one or a few depressive symptoms (e.g.…”

Section: Sex Differences In Animal Models Of Depressionmentioning

confidence: 99%

Sex differences in animal models of psychiatric disorders

Kokras

Dalla

2014

British J Pharmacology

359

187

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Psychiatric disorders are characterized by sex differences in their prevalence, symptomatology and treatment response. Animal models have been widely employed for the investigation of the neurobiology of such disorders and the discovery of new treatments. However, mostly male animals have been used in preclinical pharmacological studies. In this review, we highlight the need for the inclusion of both male and female animals in experimental studies aiming at gender-oriented prevention, diagnosis and treatment of psychiatric disorders. We present behavioural findings on sex differences from animal models of depression, anxiety, post-traumatic stress disorder, substance-related disorders, obsessive-compulsive disorder, schizophrenia, bipolar disorder and autism. Moreover, when available, we include studies conducted across different stages of the oestrous cycle. By inspection of the relevant literature, it is obvious that robust sex differences exist in models of all psychiatric disorders. However, many times results are conflicting, and no clear conclusion regarding the direction of sex differences and the effect of the oestrous cycle is drawn. Moreover, there is a lack of considerable amount of studies using psychiatric drugs in both male and female animals, in order to evaluate the differential response between the two sexes. Notably, while in most cases animal models successfully mimic drug response in both sexes, test parameters and treatment-sensitive behavioural indices are not always the same for male and female rodents. Thus, there is an increasing need to validate animal models for both sexes and use standard procedures across different laboratories. LINKED ARTICLESThis article is part of a themed section on Animal Models in Psychiatry Research. To view the other articles in this section visit http://dx.doi.org/10. 1111/bph.2014.171.issue-20 Abbreviations 5-HTT, 5-HT transporter; 8-OH-DPAT, 7-(Dipropylamino)-5,6,7,8-tetrahydronaphthalen-1-ol; Akt1, V-akt murine thymoma viral oncogene homologue 1; BDNF, brain-derived neurotrophic factor; BTBR, BTBR T + tf/J; CMS, chronic mild stress; COMT, catechol-O-methyltransferase-deficient mice; CR, conditioned response; CRF, corticotrophinreleasing factor; CS, conditioned stimulus; D1 receptor, dopamine 1 receptor; D2 receptor, dopamine 2 receptor; DISC1, disrupted-in-schizophrenia 1; Ehmt1, euchromatin histone methyltransferase 1; FBGRKO, forebrain glucocorticoid type II receptor (NR3C1) knockout; FSL, flinders sensitive rat line; FST, forced swim test; GSK3, glycogen synthase kinase 3; HAB, high anxiety-related behaviour rats; ICSS, intracranial self-stimulation; LAB, low anxiety-related behaviour rats; LI, latent inhibition; Mthfr, methylenetetrahydrofolate reductase; OCD, obsessive-compulsive disorder; PPI, prepulse inhibition; PTSD, post-traumatic stress disorder; SSRI, selective 5-HT re-uptake inhibitors; US, unconditioned stimulus; WKY, Wistar Kyoto IntroductionThe total disease burden for neuropsychiatric disorders in the European Union has been recently ...

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“…MDD symptoms are characterized by overall emotion dysregulation, low mood, anhedonia, and poor affect, among others [3]. Current treatments are only effective at inducing remission in a portion of the population [4], and men and women respond differently to pharmacological treatment [5]. Cross-cultural epidemiological studies that control for reporting biases have found that depression affects women at twice the rate that it affects men.…”

Section: Introductionmentioning

confidence: 99%

Sex-Specific Effects of Stress on Mood-Related Gene Expression

et al. 2019

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Women are twice as likely as men to be diagnosed with major depressive disorder (MDD). Recent studies report distinct molecular changes in depressed men and women across mesocorticolimbic brain regions. However, it is unclear which sex-related factors drive distinct MDD-associated pathology. The goal of this study was to use mouse experimental systems to investigate sex-specific mechanisms underlying the distinct molecular profiles of MDD in men and women. We used unpredictable chronic mild stress to induce an elevated anxiety-/depressive-like state and “four core genotypes” (FCG) mice to probe for sex-specific mechanisms. As predicted, based on previous implications in mood, stress impacted the expression of several dopamine-, GABA-, and glutamate-related genes. Some of these effects, specifically in the prefrontal cortex, were genetic sex-specific, with effects in XX mice but not in XY mice. Stress also impacted gene expression differently across the mesocorticolimbic circuit, with increased expression of mood-related genes in the prefrontal cortex and nucleus accumbens, but decreased expression in basolateral amygdala. Our results suggest that females are sensitive to the effects of chronic stress, partly due to their genetic sex, independent of gonadal hormones. Furthermore, these results point to the prefrontal cortex as the node in the mesocorticolimbic circuitry with the strongest female-specific effects.

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Sex Differences in Antidepressant Response in Recent Antidepressant Clinical Trials

Cited by 215 publications

References 22 publications

Serotonin and arginine–vasopressin mediate sex differences in the regulation of dominance and aggression by the social brain

Serotonin and arginine–vasopressin mediate sex differences in the regulation of dominance and aggression by the social brain

Sex differences in animal models of psychiatric disorders

Sex-Specific Effects of Stress on Mood-Related Gene Expression

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