Elias Eriksson

Genetic variation in the vasopressin receptor 1a gene (AVPR1A) associates with pair-bonding behavior in humans

Pair-bonding has been suggested to be a critical factor in the evolutionary development of the social brain. The brain neuropeptide arginine vasopressin (AVP) exerts an important influence on pair-bonding behavior in voles. There is a strong association between a polymorphic repeat sequence in the 5′ flanking region of the gene (avpr1a) encoding one of the AVP receptor subtypes (V1aR), and proneness for monogamous behavior in males of this species. It is not yet known whether similar mechanisms are important also for human pair-bonding. Here, we report an association between one of the human AVPR1A repeat polymorphisms (RS3) and traits reflecting pair-bonding behavior in men, including partner bonding, perceived marital problems, and marital status, and show that the RS3 genotype of the males also affects marital quality as perceived by their spouses. These results suggest an association between a single gene and pair-bonding behavior in humans, and indicate that the well characterized influence of AVP on pair-bonding in voles may be of relevance also for humans.

The serotonin reuptake inhibitor paroxetin is superior to the noradrenaline reuptake inhibitor maprotiline in the treatment of premenstrual syndrome

Recent studies indicate that antidepressant drugs with potent serotonin reuptake inhibiting properties are effective in reducing the symptoms of premenstrual syndrome (PMS). In order to elucidate whether all antidepressant drugs are equally effective in the treatment of PMS or whether potent serotonin reuptake inhibition is a prerequisite for reducing premenstrual complaints, women suffering from severe PMS were treated daily for three menstrual cycles with a selective serotonin reuptake inhibitor, paroxetine (n = 22), or with a selective noradrenaline reuptake inhibitor, maprotiline (n = 21); in addition, a placebo group was included (n = 22). Six symptoms (irritability, depressed mood, tension/anxiety, increased appetite/craving for carbohydrates, bloating, and breast tenderness) were rated by the participants daily throughout the study. With respect to all outcome measurements, the symptom reduction obtained with paroxetine was significantly superior to that obtained with placebo; with respect to irritability, increased appetite/carbohydrate craving, bloating, and breast tenderness, as well as global self-rating, paroxetine was significantly superior also to maprotiline. The clear-cut superiority of paroxetine over maprotiline indicates that not all antidepressant drugs are equally effective in the treatment of PMS; rather, like panic disorder and obsessive compulsive disorder, but in contrast to depression, PMS apparently responds better to serotonin reuptake inhibitors than to antidepressants with a noradrenergic profile.

A Link between Serotonin-Related Gene Polymorphisms, Amygdala Activity, and Placebo-Induced Relief from Social Anxiety

Placebo may yield beneficial effects that are indistinguishable from those of active medication, but the factors underlying proneness to respond to placebo are widely unknown. Here, we used functional neuroimaging to examine neural correlates of anxiety reduction resulting from sustained placebo treatment under randomized double-blind conditions, in patients with social anxiety disorder. Brain activity was assessed during a stressful public speaking task by means of positron emission tomography before and after an 8 week treatment period. Patients were genotyped with respect to the serotonin transporter-linked polymorphic region (5-HTTLPR) and the G-703T polymorphism in the tryptophan hydroxylase-2 (TPH2) gene promoter. Results showed that placebo response was accompanied by reduced stress-related activity in the amygdala, a brain region crucial for emotional processing. However, attenuated amygdala activity was demonstrable only in subjects who were homozygous for the long allele of the 5-HTTLPR or the G variant of the TPH2 G-703T polymorphism, and not in carriers of short or T alleles. Moreover, the TPH2 polymorphism was a significant predictor of clinical placebo response, homozygosity for the G allele being associated with greater improvement in anxiety symptoms. Path analysis supported that the genetic effect on symptomatic improvement with placebo is mediated by its effect on amygdala activity. Hence, our study shows, for the first time, evidence of a link between genetically controlled serotonergic modulation of amygdala activity and placebo-induced anxiety relief.

Citalopram in Premenstrual Dysphoria: Is Intermittent Treatment During Luteal Phases More Effective Than Continuous Medication Throughout the Menstrual Cycle?

In a double-blind trial, the selective serotonin reuptake inhibitor citalopram was administered to women with severe irritability and/or depressed mood in the luteal but not in the follicular phase of the menstrual cycle (premenstrual dysphoria). Treatment continued for three consecutive menstrual cycles. One group (N = 17 completers) was administered citalopram continuously at a constant dosage (20+/-10 mg/day) throughout the menstrual cycle. A second group (N = 17) also received citalopram continuously throughout the cycle, but at a lower dosage in the follicular phases (5 mg/day) than in the luteal phases (20+/-10 mg/day) (semi-intermittent treatment). A third group (N = 18) received citalopram (20+/-10 mg/day) in the luteal phase only and placebo during the follicular phase (intermittent treatment). A fourth group (N = 17) received placebo throughout the cycles. The side effects of active treatment were generally mild and transient. Intermittent administration of citalopram was clearly more effective than placebo with respect to both reduction in self-rated irritability and self-rated global improvement; it is of interest that intermittent treatment with citalopram also seemed more effective than continuous or semi-intermittent administration of the drug.

Effect of buspirone on sexual dysfunction in depressed patients treated with selective serotonin reuptake inhibitors.

To evaluate the possible influence of buspirone on sexual dysfunction in depressed patients treated with a selective serotonin reuptake inhibitor (SSRI), we analyzed data from a placebo-controlled trial designed to explore the efficacy of buspirone as add-on treatment for patients not responding to an SSRI alone. At baseline, all patients met the criteria for a major depressive episode according to DSM-IV and had received citalopram or paroxetine during a minimum of 4 weeks without responding to the treatment. Buspirone (flexible dosage, 20-60 mg/day) or placebo was added to the SSRI for 4 weeks; the mean daily dose of buspirone at endpoint was 48.5 mg (SD = 1.0). Sexual dysfunction was evaluated using a structured interview. Before starting medication with buspirone or placebo, 40% (47 of 117) reported at least one kind of sexual dysfunction (decreased libido, ejaculatory dysfunction, orgasmic dysfunction). During the 4 weeks of treatment, approximately 58% of subjects treated with buspirone reported an improvement with respect to sexual function; in the placebo group, the response rate was 30%. The difference between placebo and active drug treatment was more pronounced in women than in men. The response was obvious during the first week, with no further improvement during the course of the study. It is suggested that the effect of buspirone on sexual dysfunction is a result of a reversal of SSRI-induced sexual side effects rather than of an antidepressant effect of the drug.

Clomipramine administered during the luteal phase reduces the symptoms of premenstrual syndrome : a placebo-controlled trial

In a previous controlled trial we have shown that premenstrual irritability and depressed mood (premenstrual syndrome) can be effectively reduced by low doses of the potent (but nonselective) serotonin reuptake inhibitor clomipramine taken each day of the menstrual cycle. The present study was undertaken to examine to what extent intermittent administration of domipramine, during the luteal phase only, is also effective against premenstrual complaints. Twenty-nine undepressed women displaying severe premenstrual irritablity and/or depressed mood and fulfilling the DSM-III-R criteria of late luteal phase dysphoric disorder were treated daily from the day of ovulation until the onset of the menstruation either with clomipramine (25 to 75 mg) (n = 15) or with placebo (n = 14) for three consecutive menstrual cycles; another nine subjects (seven on domipramine, two on placebo) dropped out during treatment. In both treatment groups self-rated premenstrual irritability and depressed mood (as registered daily using a visual analogue scale) were significantly reduced during treatment; in the placebo group, this symptom reduction was about 45%, whereas in the clomipramine group it was greater than 70%. The mean premenstrual ratings of irritability and depressed mood during the three treatment cycles were significantly lower in the clomipramine group than in the placebo group. Also with respect to the rating of global improvement, the result obtained with clomipramine was significantly better than that obtained with placebo. The study confirms the previously reported effectiveness of low doses of clomipramine in the treatment of premenstrual syndrome and demonstrates that the time lag between onset of medication and clinical effect is shorter when clomipramine is used for premenstrual syndrome than when it is used for depression, panic disorder, or obsessive compulsive disorder.

Clomipramine effectively reduces premenstrual irritability and dysphoria : a placebo-controlled trial

Forty nondepressed women displaying severe premenstrual irritability and/or dysphoria and fulfilling the DSM‐III‐R criteria of late luteal phase dysphoric disorder were treated daily for 3 menstrual cycles with either the potent serotonin reuptake inhibitor clomipramine (25–75 mg; flexible dosage) (n= 20) or placebo (n= 20). In both treatment groups premenstrual irritability and dysphoria (as rated daily by the patients using a visual analogue scale) were significantly reduced as compared with the rating during 2 pretreatment reference cycles; however, in the placebo group this reduction was only about 40% whereas, in the clomipramine group, the symptom decrease was >80%. At all 3 treatment cycles, patients on clomipramine displayed significantly lower symptom rating than controls. Also with respect to the rating of global improvement, the results obtained with clomipramine were considerably and significantly better than those obtained with placebo. It is concluded that low doses of clomipramine effectively reduce premenstrual irritability and dysphoria with a response rate close to 100%. The possible role of serotonin in the pathophysiology of the premenstrual syndrome is discussed.

Catechol O -Methyltransferase Val 158 Met Polymorphism is Associated with Cognitive Performance in Nondemented Adults

The catechol O-methyltransferase (COMT) gene is essential in the metabolic degradation of dopamine in the prefrontal cortex. In the present study, we examined the effect of a Val158Met polymorphism in the COMT gene on individual differences and changes in cognition (executive functions and visuospatial ability) in adulthood and old age. The participants were 292 nondemented men (initially aged 35-85 years) from a random sample of the population (i.e., the Betula study) tested at two occasions with a 5-year interval. Confirmatory factor analyses were used to test the underlying structure of three indicators of executive functions (verbal fluency, working memory, and Tower of Hanoi). Associations between COMT, age, executive functioning, and visuospatial (block design) tasks were examined using repeated-measures analyses of variance. Carriers of the Val allele (with higher enzyme activity) compared with carriers of the Met/Met genotype (with low enzyme activity) performed worse on executive functioning and visuo-spatial tasks. Individuals with the Val/Val genotype declined in executive functioning over the 5-year period, whereas carriers of the Met allele remained stable in performance. An Age COMT interaction for visuospatial ability located the effect for middle-aged men only. This COMT polymorphism is a plausible candidate gene for executive functioning and fluid intelligence in nondemented middle-aged and older adults.

Rat brain serotonin: biochemical and functional evidence for a sex difference.

Male and female rats were compared with respect to brain serotonin (5-HT) levels, synthetic capacity, receptor sensitivity, and CNS functions. Levels of whole brain 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) were higher in females. The accumulation of 5-HT after treatment with the monoamine oxidase inhibitor pargyline alone and in combination with the 5-HT precursor L-tryptophan was greater in females than in males. 5-HT increased and 5-HIAA decreased to the same extent in both sexes after administration of the 5-HT agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). The temperature fall after all drug treatments was greater in females, but the “5-HT behavioural syndrome” was more pronounced in females merely after pargyline plus tryptophan; the behavioural response after 8-OH-DPAT did not differ between the sexes. These results are indicative of sex differences in the brain 5-HT neuronal systems. They are discussed in relation to differences between males and females in sexual behaviour, aggression and affective disorders.

Towards a consensus on diagnostic criteria, measurement and trial design of the premenstrual disorders : the ISPMD Montreal consensus

Premenstrual disorders (PMD) are characterised by a cluster of somatic and psychological symptoms of varying severity that occur during the luteal phase of the menstrual cycle and resolve during menses (Freeman and Sondheimer, Prim Care Companion J Clin Psychiatry 5:30–39, 2003; Halbreich, Gynecol Endocrinol 19:320–334, 2004). Although PMD have been widely recognised for many decades, their precise cause is still unknown and there are no definitive, universally accepted diagnostic criteria. To consider this issue, an international multidisciplinary group of experts met at a face-to-face consensus meeting to review current definitions and diagnostic criteria for PMD. This was followed by extensive correspondence. The consensus group formally became established as the International Society for Premenstrual Disorders (ISPMD). The inaugural meeting of the ISPMD was held in Montreal in September 2008. The primary aim was to provide a unified approach for the diagnostic criteria of PMD, their quantification and guidelines on clinical trial design. This report summarises their recommendations. It is hoped that the criteria proposed here will inform discussions of the next edition of the World Health Organisation’s International Classification of Diseases (ICD-11), and the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-V) criteria that are currently under consideration. It is also hoped that the proposed definitions and guidelines could be used by all clinicians and investigators to provide a consistent approach to the diagnosis and treatment of PMD and to aid scientific and clinical research in this field.