Neural correlates of instrumental responding in the context of alcohol-related cues index disorder severity and relapse risk.

The influence of Pavlovian conditioned stimuli on ongoing behavior may contribute to explaining how alcohol cues stimulate drug seeking and intake. Using a Pavlovian-instrumental transfer task, we investigated the effects of alcohol-related cues on approach behavior (i.e., instrumental response behavior) and its neural correlates, and related both to the relapse after detoxification in alcohol-dependent patients. Thirty-one recently detoxified alcohol-dependent patients and 24 healthy controls underwent instrumental training, where approach or non-approach towards initially neutral stimuli was reinforced by monetary incentives. Approach behavior was tested during extinction with either alcohol-related or neutral stimuli (as Pavlovian cues) presented in the background during functional magnetic resonance imaging (fMRI). Patients were subsequently followed up for 6 months. We observed that alcohol-related background stimuli inhibited the approach behavior in detoxified alcohol-dependent patients (t = - 3.86, p < .001), but not in healthy controls (t = - 0.92, p = .36). This behavioral inhibition was associated with neural activation in the nucleus accumbens (NAcc) (t(30) = 2.06, p < .05). Interestingly, both the effects were only present in subsequent abstainers, but not relapsers and in those with mild but not severe dependence. Our data show that alcohol-related cues can acquire inhibitory behavioral features typical of aversive stimuli despite being accompanied by a stronger NAcc activation, suggesting salience attribution. The fact that these findings are restricted to abstinence and milder illness suggests that they may be potential resilience factors.Clinical trial: LeAD study, http://www.lead-studie.de , NCT01679145.

Effects of rivastigmine on actigraphically monitored motor activity in severe agitation related to Alzheimer's disease: a placebo-controlled pilot study.

Acetylcholinesterase inhibitors (AChEIs) are effective in the treatment of cognitive symptoms in Alzheimer's disease (AD). Because the behavioral and psychological symptoms of dementia (BPSD) have also been attributed to central cholinergic deficits, we examined whether the AChEI rivastigmine can reduce motor activity as measured in a rater-independent manner by wrist actigraphy in agitated AD patients. A total of 20 consecutive AD inpatients (13 females, 7 males, 80.4+/-9.1 years, S.D.) were included from our geriatric psychiatry unit, all of whom were exhibiting agitated behavior not attributable to delirium. Patients were assigned randomly and in a single-blinded fashion to rivastigmine 3mg or placebo for 14 days. Motor activity levels were monitored using an actigraph worn continuously on the wrist of the non-dominant hand. At the beginning and end of the study, patients were assessed using the Neuropsychiatric Inventory (NPI) and Nurses' Observation Scale for Geriatric Patients (NOSGER). Patients in the rivastigmine group exhibited less agitation than placebo recipients on the NPI-agitation subscale, but not on NOSGER. Actigraphic measurements showed a tendency towards reduced motor activity in the rivastigmine group. Because rivastigmine usually exerts its main effects after a longer period of time, the short-term effects seen in our study justify further controlled clinical trials examining the use of rivastigmine in BPSD by means of actigraphy.

Delta-9-tetrahydrocannabinol for nighttime agitation in severe dementia.

RATIONALE: Nighttime agitation occurs frequently in patients with dementia and represents the number one burden on caregivers today. Current treatment options are few and limited due to substantial side effects. OBJECTIVES: The aim of the study was to measure the effect of the cannabinoid dronabinol on nocturnal motor activity. METHODS: In an open-label pilot study, six consecutive patients in the late stages of dementia and suffering from circadian and behavioral disturbances-five patients with Alzheimer's disease and one patient with vascular dementia-were treated with 2.5 mg dronabinol daily for 2 weeks. Motor activity was measured objectively using actigraphy. RESULTS: Compared to baseline, dronabinol led to a reduction in nocturnal motor activity (P=0.028). These findings were corroborated by improvements in Neuropsychiatric Inventory total score (P=0.027) as well as in subscores for agitation, aberrant motor, and nighttime behaviors (P<0.05). No side effects were observed. CONCLUSIONS: The study suggests that dronabinol was able to reduce nocturnal motor activity and agitation in severely demented patients. Thus, it appears that dronabinol may be a safe new treatment option for behavioral and circadian disturbances in dementia.

Association between response to lithium augmentation and the combined DEX/CRH test in major depressive disorder.

Although lithium augmentation is the foremost and most well-documented treatment strategy for treatment resistant depression, knowledge of factors related to response remains scanty. Findings with the combined dexamethasone/corticotropin-releasing hormone (DEX/CRH) test are associated with response to treatment with a tricyclic antidepressant. This study investigated the potential predictive value of the DEX/CRH test for lithium augmentation response in major depressive disorder. The DEX/CRH test was conducted prior to lithium augmentation in 30 patients with a major depressive episode who had not responded to an antidepressant monotherapy trial of at least 4 weeks. Response status was assessed weekly using the Hamilton Rating Scale for Depression. For multivariate prediction, a logistic regression analysis was performed. Eleven (37%) patients responded to lithium augmentation within 4 weeks. Responders showed higher ACTH response and lower cortisol response in the DEX/CRH test, but results were not statistically significant. However, non-responders had a statistically significant higher cortisol/ACTH peak ratio (3.43+/-1.75) compared to responders (2.18+/-1.38) (P=0.027). This ratio is an indicator for the sensitivity of the adrenal cortex to ACTH. A cortisol/ACTH peak ratio of 1.8 was identified as the best cutoff point to differentiate responders from non-responders. In conclusion, results suggest a more sensitive adrenal cortex in non-responders to lithium augmentation. The findings would be in line with the assumption of a more chronic course of depression with more pronounced biological alterations in the non-responder group, because chronic depression is known to cause enlargement of the adrenal gland with a subsequent hypersensitivity to ACTH. Results of this study should be confirmed in a larger study group.

Hypothalamic-pituitary-thyroid system activity during lithium augmentation therapy in patients with unipolar major depression.

OBJECTIVE: Lithium augmentation is an established strategy in the treatment of refractory depression, but little is known about predictors of response and its mode of action. There is increasing evidence that low thyroid function indices within the normal range are associated with a poorer treatment response to antidepressants, but previous studies on the hypothalamic-pituitary-thyroid (HPT) system during lithium augmentation provide inconclusive results and have methodological limitations. This study aimed at exploring the role of thyroid function in lithium augmentation and used a prospective design that included a homogeneous sample of inpatients with unipolar major depressive disorder. METHODS: In 24 euthyroid patients with a major depressive episode who had not responded to antidepressant monotherapy of at least 4 weeks, we measured serum thyroid-stimulating hormone (TSH), total triiodothyronine (T3) and total thyroxine (T4) before (baseline) and during lithium augmentation therapy (follow-up). The time point of the endocrinological follow-up depended on the status of response, which was assessed weekly with the Hamilton Depression Rating Scale, 17-item version (HDRS17). Responders were reassessed immediately after response was determined, and non-responders after 4 weeks of lithium augmentation. RESULTS: There was a statistically significant change in thyroid system activity during lithium augmentation, with an increase of TSH levels and a decrease of peripheral T3 and T4 levels. However, there were no differences in any of the HPT hormones between responders and non-responders at baseline or at follow-up. CONCLUSIONS: The decrease of thyroid system activity during lithium treatment reflects the well-established "antithyroid" properties of lithium. However, it appears that thyroid status does not predict response to lithium augmentation in euthyroid patients before treatment.

Lithium augmentation increases post-dexamethasone cortisol in the dexamethasone suppression test in unipolar major depression.

Although considerable evidence exists on the efficacy of lithium as an augmenting agent in refractory depression, the underlying neurobiology of this phenomenon is unknown. In patients with major depression, changes of the hypothalamic-pituitary-adrenocortical (HPA) system have been detected by means of the dexamethasone suppression test (DST), when administered during treatment with tricyclic antidepressants. We investigated whether the DST also reveals alterations of the HPA system during lithium augmentation. We also sought to identify whether response to lithium augmentation can be predicted with the DST. Twenty-five patients with unipolar major depression, who did not respond to an adequate antidepressant monotherapy of at least 4 weeks, were measured for basal (pre-dexamethasone, 0800h) cortisol and ACTH levels and were administered the DST the day before initiation of lithium augmentation treatment. The same neuroendocrine procedures were repeated after 3 to 4 weeks. Criteria of response to lithium augmentation, defined as a reduction of the Hamilton Depression Rating Scale (HDRS17) score by > or =50% and an end point score of 9 or less, were determined by weekly HDRS ratings. The DST revealed a statistically significant increase of the post-dexamethasone cortisol values (P = 0.021) and an increase in the post-dexamethasone ACTH values (P = 0.051) during lithium augmentation as compared to pre-treatment baseline evaluations. The pre-dexamethasone hormone values were unchanged. The number of non-suppressors at baseline was one and increased to three at follow-up. Results of DST did not predict response to lithium augmentation, which occurred in 40% of subjects. Results suggest that lithium augmentation increases HPA system activity, as indicated by the increase of post-dexamethasone cortisol and ACTH levels measured by the DST. This is in contrast to the established decline of HPA system activity during treatment with tricyclic antidepressants.

Lithium augmentation increases the ACTH and cortisol response in the combined DEX/CRH test in unipolar major depression.

Lithium augmentation is a well established strategy for treatment-resistant depression. The exact mode of its action is unknown, but an enhancement of serotonergic transmission is hypothesized. The authors investigated changes in the hypothalamic-pituitary-adrenocortical (HPA) system during lithium augmentation and their correlation to clinical response by means of the combined dexamethasone/CRH test (DEX/CRH test). Thirty patients with unipolar major depressive episodes (DSM IV) who had not responded to an adequate trial with an antidepressant were assessed on the day before lithium augmentation (baseline) with the DEX/CRH test (pretreatment with 1.5 mg dexamethasone p.o. at 11 P.M. and CRH stimulation at 3 P.M. on the next day). Twenty-four patients were re-assessed after response was determined or, in cases of non-response, four weeks after initiation of lithium augmentation. Response to lithium augmentation was measured by weekly ratings on the Hamilton Depression Rating Scale (HDRS 17-item version). Response was defined as a DeltaHDRS of > or =50% and an endpoint score of < 10. Patients had a significantly higher ACTH and cortisol response to CRH stimulation during lithium augmentation compared with the values at baseline. There was no difference in ACTH and cortisol reaction between responders and non-responders to lithium augmentation. This increase is in contrast to the known normalization of HPA-axis overdrive after treatment with a tricyclic antidepressant like amitriptyline. Because the effect was independent of response status we suggest that this increase reflects an effect of lithium that is independent from the psychopathological state or its change. This effect might be explained by the serotonergic effects of lithium.