Ecstasy use and depression: A 4-year longitudinal study among an Australian general community sample

Rationale

Longitudinal, population-based studies can better assess the relationship of ecstasy use with depression.

Objectives

We examined whether change in ecstasy use was associated with change in depressive symptoms/probable depression over a 4-year period, among a large Australian sample.

Methods

The Personality and Total Health project is a longitudinal general community study of Australians from Canberra and Queanbeyan. Data from the youngest cohort when aged 24-30 (N?=?2, 128) and 4 years later (N?=?1, 977) was included. The Goldberg depression scale and the Brief Patient Health Questionnaire measured depressive symptoms and probable depression, respectively. Multilevel growth models also considered demographics, psychosocial characteristics, and other drug use.

Results

Ecstasy use was not associated with long-term depressive symptoms or greater odds of depression in multivariate analyses. Users had more self-reported depressive symptoms when using ecstasy compared to not using. However, differences between people who had and had not ever used ecstasy largely accounted for this. Other factors were more important in the prediction of depression.

Conclusions

It would be premature to conclude that ecstasy use is not related to the development of long-term depressive symptoms, given the relatively low level of ecstasy and other drug use in this community sample. Results showed that other factors need to be considered when investigating ecstasy use and depression.     

Cushing’s syndrome diagnosed after delivery: a case report

Introduction

During normal pregnancy there are significant changes in hypothalamic-pituitary-adrenal axis, with increased levels of plasma cortisol and adrenocorticotropic hormone which sometimes reach values observed in patients with Cushing’s syndrome. Cushing’s syndrome (CS) is rarely encountered during pregnancy, but is associated with serious maternal and fetal complications.

Case presentation

A 31-year-old female was admitted to our institution four weeks after delivery. Physical examination revealed moon face, purple striae throughout the abdomen, bruising over the legs, a dorsocervical fat pad and hirsutism. She delivered a eutrophic preterm newborn at 34 weeks gestation, without any maternal or fetal complications during delivery. Imaging showed a mass in the right suprarenal gland with a normal pituitary. After four weeks the patient underwent a right adrenalectomy. The mass was eventually identified as an adrenocortical adenoma.

Conclusion

In our case the diagnosis of CS was established only after pregnancy, which enabled the development of numerous adverse consequences secondary to increased plasma cortisol. If CS is recognized during pregnancy, treatment and its timing could be carefully chosen according to the patient’s individual characteristics.     

Central nervous system effects of prenatal selective serotonin reuptake inhibitors: sensing the signal through the noise

Rationale

Women are increasingly prescribed selective serotonin reuptake inhibitors (SSRIs) during pregnancy, with potential implications for neurodevelopment. Whether prenatal SSRI exposure has an effect on neurodevelopment and behavior in the offspring is an important area of investigation.

Objectives

The aim of this paper was to review the existing preclinical and clinical literature of prenatal SSRI exposure on serotonin-related behaviors and markers in the offspring. The goal is to determine if there is a signal in the literature that could guide clinical care and/or inform research.

Results

Preclinical studies (n?=?4) showed SSRI exposure during development enhanced depression-like behavior. Half of rodent studies examining anxiety-like behavior (n?=?13) noted adverse effects with SSRI exposure. A majority of studies of social behavior (n?=?4) noted a decrease in sociability in SSRI exposed offspring. Human studies (n?=?4) examining anxiety in the offspring showed no adverse effects of prenatal SSRI exposure. The outcome of one study suggested that children with autism were more likely to have a mother who was prescribed an SSRI during pregnancy.

Conclusions

Preclinical findings in rodents exposed to SSRIs during development point to an increase in depression- and anxiety-like behavior and alteration in social behaviors in the offspring, though both the methods used and the findings were not uniform. These data are not robust enough to discourage use of SSRIs during human pregnancy, particularly given the known adverse effects of maternal mental illness on pregnancy outcomes and infant neurodevelopment. Future research should focus on consistent animal models and prospective human studies with larger samples.     

Prenatal exposure to escitalopram and/or stress in rats

Rationale

A rigorously investigated model of stress and antidepressant administration during pregnancy is needed to evaluate possible effects on the mother.

Objective

The objective of this study was to develop a model of clinically relevant prenatal exposure to an antidepressant and stress during pregnancy to evaluate the effects on maternal care behavior.

Results

Female rats implanted with 28-day osmotic minipumps delivering the SSRI escitalopram throughout pregnancy had serum escitalopram concentrations in a clinically observed range (17–65 ng/ml). A separate cohort of pregnant females exposed to a chronic unpredictable mild stress paradigm on gestational days 10–20 showed elevated baseline (305 ng/ml), and acute stress-induced (463 ng/ml), plasma corticosterone concentrations compared to unstressed controls (109 ng/ml). A final cohort of pregnant dams were exposed to saline (control), escitalopram, stress, or stress and escitalopram to determine the effects on maternal care. Maternal behavior was continuously monitored over the first 10 days after parturition. A reduction of 35 % in maternal contact and 11 % in nursing behavior was observed due to stress during the light cycle. Licking and grooming behavior was unaffected by stress or drug exposure in either the light or dark cycle.

Conclusions

These data indicate that: (1) clinically relevant antidepressant treatment during human pregnancy can be modeled in rats using escitalopram; (2) chronic mild stress can be delivered in a manner that does not compromise fetal viability; and (3) neither of these prenatal treatments substantially altered maternal care post parturition.     

Changes in the prescribing pattern of antidepressant drugs in elderly patients: an Italian,nationwide, population-based study

Background

Despite the high use of antidepressants (ADs) among the elderly, there is limited information about the prescribing pattern of these drugs in the Italian elderly population. The aim of this study was to analyze the trend in the use of ADs in the Italian elderly patients in the years 2003-2009, and specifically, to evaluate rates and predictors of AD treatment discontinuation in depressed older patients.

Methods

The nationwide general practice Health Search Database (HSD) was used to identify AD users aged 65 years old and over from 2003 to 2009. ADs were categorized as (1) selective serotonin reuptake inhibitors (SSRIs); (2) serotonin-norepinephrine reuptake inhibitors (SNRIs); (3) tricyclic antidepressants (TCAs); (4) noradrenergic and specific serotonergic antidepressants (NaSSAs); and (5) other ADs. Incidence and prevalence of AD use per 1,000 inhabitants was calculated by drug class and single compound. We also measured rates and predictors of AD discontinuation (i.e., treatment gap?≥?60 days) during the first year of therapy.

Results

Overall, 39,557 AD users ≥65 years (17 % of the total HSD elderly population) were included in the study. SSRIs were increasingly and most frequently prescribed ADs (102.7-195.3 per 1,000 over seven years). The most common indications for AD use were depression and anxiety. Overall, 14 % of AD users continued their AD medication without treatment gaps, 27 % were intermittent AD users and 58 % discontinued their ADs during the first year of follow-up. Specific AD classes such as TCAs and ‘other ADs were found to be predictors of discontinuation. In depressed patients, the use of NaSSas, TCAs and ‘other ADs as well the concomitant use of >5 drugs (other than ADs) and living in Southern Italy were more likely to predict discontinuation.

Conclusion

ADs, especially SSRIs, are widely and increasingly prescribed in elderly Italian patients in recent years. The observed high AD discontinuation rates are likely to impact the achievement of a therapeutic endpoint in depressed patients. Patients who are at high risk of AD discontinuation such as those receiving multi-drug therapy or living in Southern Italy should be monitored more closely to improve benefits of AD treatments.     

Pharmacologic evidence to support clinical decision making for peripartum methadone treatment

Rationale

Limited pharmacological data are available to guide methadone treatment during pregnancy and postpartum.

Objectives

Study goals were to (1) characterize changes in methadone dose across childbearing, (2) determine enantiomer-specific methadone withdrawal kinetics from steady state during late pregnancy, (3) assess enantiomer-specific changes in methadone level/dose (L/D) ratios across childbearing, and (4) explore relationships between CYP2B6, CYP2C19, and CYP3A4 single-nucleotide polymorphisms and maternal dose, plasma concentration, and L/D.

Methods

Methadone dose changes and timed plasma samples were obtained for women on methadone (n?=?25) followed prospectively from third trimester of pregnancy to 3 months postpartum.

Results

Participants were primarily white, Medicaid insured, and multiparous. All women increased their dose from first to end of second trimester (mean peak increase?=?23 mg/day); 71 % of women increased from second trimester to delivery (mean peak increase?=?19 mg/day). Half took a higher dose 3 months postpartum than at delivery despite significantly larger clearance during late pregnancy. Third trimester enantiomer-specific methadone half-lives (range R-methadone 14.7–24.9 h; S-methadone, 8.02–18.9 h) were about half of those reported in non-pregnant populations. In three women with weekly 24-h methadone levels after delivery, L/D increased within 1–2 weeks after delivery. Women with the CYP2B6 Q172 variant GT genotype have consistently higher L/D values for S-methadone across both pregnancy and postpartum.

Conclusions

Most women require increases in methadone dose across pregnancy. Given the shorter half-life and larger clearances during pregnancy, many pregnant women may benefit from split methadone dosing. L/D increases quickly after delivery and doses should be lowered rapidly after delivery.     

Leveraging Physiological Data from Literature into a Pharmacokinetic Model to Support Informative Clinical Study Design in Pregnant Women

Purpose

Physiological changes during pregnancy can effect pharmacokinetic (PK) parameters, which may lead to altered dose requirements. We aimed to leverage literature-based physiological changes during pregnancy into a PK model and compare its performance to a published reference model in pregnant women and to use the literature-based model to determine informative PK sampling times for a clinical study that aims to quantify the PK of enoxaparin throughout pregnancy.

Methods

Changes in total body water (BW) and creatinine clearance (CRCL) during pregnancy were described using regression models. BW and CRCL were linked to a PK model of enoxaparin in non-pregnant women. Performance of the literature-based PK model was compared to a previously published empirical reference model. D-optimal sampling times were determined and evaluated for literature-based and reference models.

Results

The literature-based model adequately predicted anti-Xa plasma concentrations when compared to reference model predictions. An informative sampling design was succesfully developed, with parameters expected with good precision (RSE?Conclusion A literature-based model describing enoxaparin PK during pregnancy was developed and evaluated. The modelling framework could be used to support development of informative designs in pregnancy when prior models are unavailable.     

Antidepressant use and glycemic control

Rationale

Past research on the association of antidepressant medication use with glycemic control abnormalities has produced mixed results.

Objective

To examine the association of antidepressant use with glycemic control abnormalities and screen-positive diabetes in a representative population sample of US adults without a diagnosis of diabetes.

Methods

Using data from adult participants of the National Health and Nutrition Examination Survey (NHANES, 2005–2010), the association of antidepressant use with continuous measures of HbA1c, fasting blood sugar, 2-h oral glucose tolerance test, insulin sensitivity and screen-positive diabetes according to HbA1c, fasting blood sugar and 2-h oral glucose tolerance test were assessed.

Results

Antidepressant use was not associated with increased levels of HbA1c, fasting blood sugar, 2-h oral glucose tolerance test, reduced insulin sensitivity or increased prevalence of screen-positive diabetes. Results were mostly consistent across sociodemographic groups and across different lengths of exposure, different classes of antidepressants and levels of body mass index.

Conclusions

In this representative population sample, antidepressant use was not associated with an increased risk of abnormalities in glycemic control or undetected diabetes. Positive findings from past research may be attributable to detection bias, in that individuals prescribed antidepressants may be more likely to be tested and diagnosed with diabetes.     

Stimulation of nicotine reward and central cholinergic activity in Sprague–Dawley rats exposed perinatally to a fat-rich diet

Rationale

While clinical studies show maternal consumption of palatable fat-rich diets during pregnancy to negatively impact the children’s behaviors and increase their vulnerability to drug abuse, the precise behavioral and neurochemical mechanisms mediating these phenomena have yet to be examined.

Objective

The study examined in rats whether gestational exposure to a high-fat diet (HFD) can increase the offspring’s propensity to use nicotine and whether disturbances in central nicotinic cholinergic signaling accompany this behavioral effect.

Methods

Rat offspring exposed perinatally to a HFD or chow diet were characterized in terms of their nicotine self-administration behavior in a series of operant response experiments and the activity of acetylcholinesterase (AChE) and density of nicotinic ACh receptors (nAChRs) in different brain areas.

Result

Perinatal HFD compared to chow exposure increased nicotine-self administration behavior during fixed ratio and dose–response testing and caused an increase in breakpoint using progressive ratio testing, while nicotine seeking in response to nicotine prime-induced reinstatement was reduced. This behavioral change induced by the HFD was associated with a significant reduction in activity of AChE in the midbrain, hypothalamus, and striatum and increased density of β2-nAChRs in the ventral tegmental area and substantia nigra and of α7-nAChRs in the lateral and ventromedial hypothalamus.

Conclusions

Perinatal exposure to a HFD increases the vulnerability of the offspring to excessive nicotine use by enhancing its reward potential, and these behavioral changes are accompanied by a stimulation of nicotinic cholinergic signaling in mesostriatal and hypothalamic brain areas important for reinforcement and consummatory behavior.     

Effect of low-dose acute tryptophan depletion on the specificity of autobiographical memory in healthy subjects with a family history of depression

Rationale

Low-dose acute tryptophan depletion (LD-ATD), while having no effect on mood, has been shown to reduce specificity of autobiographical memory in patients who have recovered from a depressive episode.

Objectives

This study aimed to explore if reduced specificity of autobiographical memory with LD-ATD is common to other groups of individuals at risk of depression, specifically a healthy population with a family history of depression.

Methods

Nineteen healthy young adults with at least one first-degree relative with a history of major depression were recruited. LD-ATD drinks containing 1.15?g of tryptophan (T+) or no tryptophan (T?) were administered on two separate occasions, in a double blind random order crossover design. The Autobiographical Memory Test (AMT) was administered 5?h after drink administration.

Results

Analysis of variance revealed a significant difference in the effects of LD-ATD drinks on plasma free tryptophan with no mood change with either drink. There was no within-subject main effect of LD-ATD on the memory task. However, there was a main effect of order of drink. Exploratory analysis of visit 1 data indicated a large between-subject effect (d?=?1.4) of LD-ATD on AMT with T? associated with less specificity in response to negative cue words (F(1, 17)?=?8.71, p?=?0.009).

Conclusions

Similar to findings following recovery from depression, LD-ATD can reduce specificity of AMT in the absence of lowered mood in healthy individuals with a strong family history of depression. These findings may reflect a 5-HT-dependent cognitive vulnerability to depression in different populations and warrant further research.     

High baseline BDNF serum levels and early psychopathological improvement are predictive of treatment outcome in major depression

Rationale

Major depressive disorder has been associated with low serum levels of brain-derived neurotrophic factor (sBDNF), which is functionally involved in neuroplasticity. Although sBDNF levels tend to normalize following psychopathological improvement with antidepressant treatment, it is unclear how closely sBDNF changes are associated with treatment outcome.

Objectives

To examine whether baseline sBDNF or early changes in sBDNF are predictive of response to therapy.

Methods

Twenty-five patients with major depressive disorder underwent standardized treatment with duloxetine. Severity of depression, measured by the Hamilton Depression Rating Scale, and sBDNF were assessed at baseline, and after 1, 2, and 6 weeks of treatment. Therapy outcome after 6 weeks was defined as response (≥50 % reduction in baseline Hamilton Depression Rating score) and remission (Hamilton Depression Rating score <8). The predictive values for treatment outcome of baseline sBDNF, and early (i.e., ≤2 weeks) changes in sBDNF and Hamilton Depression Rating score were also assessed.

Results

At baseline, sBDNF correlated with Hamilton Depression Rating scores. Treatment response was associated with a higher baseline sBDNF concentration, and a greater Hamilton Depression Rating score reduction after 1 and 2 weeks. A greater early rise in sBDNF correlated with a decreased early Hamilton Depression Rating score reduction.

Conclusions

Even though higher baseline sBDNF levels are associated with more severe depression, they may reflect an increased capacity to respond to treatment. In contrast, changes in sBDNF over the full course of treatment are not associated with psychopathological improvement.     

5-HT modulation by acute tryptophan depletion of human instrumental contingency judgements

Introduction

The concept of ??depressive realism??, that depression leads to more accurate perception of causal control, has been influential in the field of depression research, but remains controversial. Recent work testing contingency learning has suggested that contextual processing might determine realism-like effects. Serotonin (5-hydroxytryptamine, (5-HT)), which is implicated in the pathophysiology of depression, might also influence contextual processing. Using acute tryptophan depletion (ATD), we tested the hypothesis that dysfunctional serotoninergic neurotransmission influences contingency judgements in dysphoric subjects via an effect on contextual processing.

Materials and methods

We employed a novel contingency learning task to obtain separate measures (ratings) of the causal effect of partcipants?? responses and efficacy of the background context over an outcome. Participants, without a history of depression, completed this task on and off ATD in a double-blind, placebo-controlled, within-subjects design.

Results

As with other work on contingency learning, the effects of ATD were related to baseline mood levels. Although no overall effects of ATD were observed, the subgroup of participants with low Beck depression inventory (BDI) scores showed reduced ratings of contextual control and improved accuracy of contingency judgements under positive contingencies following ATD, compared to placebo. High BDI participants demonstrated low accuracy in contingency judgements, regardless of serotoninergic status.

Conclusions

No effect of ATD on contingency judgements was observed in the group as a whole, but effects were observed in a subgroup of participants with low BDI scores. We discuss these data in light of the context processing hypothesis, and prior research on 5-HT and depressive realism.     

Safety of ginger use in pregnancy: results from a large population-based cohort study

Purpose

The objective of the study was to examine the safety of ginger use during pregnancy on congenital malformations and selected pregnancy outcomes.

Methods

The Norwegian Mother and Child Cohort study, a large population-based cohort, provided the data used in this study. Our study population consisted of 68,522 women. Data on ginger use and socio-demographic factors were retrieved from three self-administered questionnaires completed by the women during weeks 17 and 30 of the pregnancy and when their child was 6 months old. Data on pregnancy outcomes were provided by the Medical Birth Registry of Norway.

Results

Among the 68,522 women in the study, 1,020 (1.5 %) women reported using ginger during pregnancy. The use of ginger during pregnancy was not associated with any increased risk of congenital malformations. No increased risk for stillbirth/perinatal death, preterm birth, low birth weight, or low Apgar score was detected for the women exposed to ginger during pregnancy compared to women who had not been exposed.

Conclusion

Use of ginger during pregnancy does not seem to increase the risk of congenital malformations, stillbirth/perinatal death, preterm birth, low birth weight, or low Apgar score. This finding is clinically important for health care professionals giving advice to pregnant women with NPV.     

The lack of association between components of metabolic syndrome and treatment resistance in depression

Rationale

Although a number of studies investigated the link between major depressive disorder (MDD) and metabolic syndrome (MetS), the association between MetS and treatment-resistant depression (TRD) is still not clear.

Objectives

The aim of the study was to investigate the relationship between TRD and MetS and/or components of MetS and cardiovascular risk factors. Given the high prevalence of both conditions, the hypothesis was that TRD would be significantly associated with MetS.

Methods

This cross-sectional study included 203 inpatients with MDD, assessed for the treatment resistance, MetS and its components, and severity of MDD. Diagnoses and evaluations were made with SCID based on DSM-IV, National Cholesterol Education Program Adult Treatment Panel III criteria, and the Hamilton Depression Rating Scale.

Results

TRD prior to study entry was found in 26.1 % of patients, while MetS was observed in 33.5 % of patients. The prevalence of MetS did not differ significantly between TRD and non-TRD patients. In addition, the frequency of the altered values of particular components of the MetS or cardiovascular risk factors was not associated with treatment resistance in depressed patients. Patients with TRD were older, had a higher number of lifetime episodes of depression and suicide attempts, and longer duration of MDD compared to non-TRD patients.

Conclusions

The occurrence of either MetS or the particular components of the MetS and other cardiovascular risk factors was similar between TRD and non-TRD patients. Although there is a bidirectional relationship between depression and MetS, neither MetS nor its components appear to influence treatment resistance to antidepressants.     

The 5-HT7 receptor and disorders of the nervous system: an overview

Rationale

The 5-HT₇ receptor is a more recently discovered G-protein-coupled receptor for serotonin. The functions and possible clinical relevance of this receptor are not yet fully understood.

Objective

The present paper reviews to what extent the use of animal models of human psychiatric and neurological disorders have implicated the 5-HT₇ receptor in such disorders. The studies have used a combination of pharmacological and genetic tools targeting the receptor to evaluate effects on behavior.

Results

Models of anxiety and schizophrenia have yielded mixed results with no clear role for the 5-HT₇ receptor described in these disorders. Some data are available for epilepsy, migraine, and pain but it is still very early to draw any definitive conclusions. There is a considerable amount of evidence supporting a role for the 5-HT₇ receptor in depression. Both blockade and inactivation of the receptor have resulted in an antidepressant-like profile in models of depression. Supporting evidence has also been obtained in sleep studies. Especially interesting are the augmented effects achieved by combining antidepressants and 5-HT₇ receptor antagonists. The antidepressant effect of amisulpride has been shown to most likely be mediated by the 5-HT₇ receptor.

Conclusions

The use of pharmacological and genetic tools in preclinical animal models strongly supports a role for the 5-HT₇ receptor in depression. Indirect evidence exists showing that 5-HT₇ receptor antagonism is clinically useful in the treatment of depression. Available data also indicate a possible involvement of the 5-HT₇ receptor in anxiety, epilepsy, pain, and schizophrenia.