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ItemChronic adrenocorticotrophic hormone treatment alters tricyclic antidepressant efficacy and prefrontal monoamine tissue levels(ELSEVIER, 2013-04-01)Several animal models are currently utilised in the investigation of major depressive disorder; however, each is validated by its response to antidepressant pharmacotherapy. Few animal models consider the notion of antidepressant treatment resistance. Chronic daily administration of adrenocorticotropic hormone (ACTH) or corticosterone can alter behavioural responses to antidepressants, effectively blocking antidepressant efficacy. Herein, we demonstrate that ACTH-(1-24) (100μg/day; 14 days) blocks the immobility-reducing 'antidepressant' effects of a single dose of imipramine (10mg/kg) in the forced swim test. This finding was accompanied by altered monoamine tissue levels in the prefrontal cortex (PFC) 1h after exposure to the acute stress of the forced swim test. PFC tissue from ACTH pre-treated animals contained significantly higher serotonin, noradrenaline and adrenaline concentrations relative to saline pre-treated controls. Conversely, dopamine levels were significantly decreased. Altered plasma corticosterone responses to ACTH injections were observed over the treatment course. Measures were taken on treatment days 1, 4, 8, 11, 14 and 15. ACTH administration initially enhanced plasma corticosterone levels, however, these normalised to levels consistent with control animals by day 14. No differences in corticosterone levels were observed across the treatment time course in saline-treated animals. Taken together these results indicate that pre-treatment with ACTH (100μg/day; 14 days) blocks the antidepressant effects of imipramine (10mg/kg), significantly alters key PFC monoamine responses to stress and downregulates glucocorticoid responses. These results suggest that chronic ACTH treatment is a promising paradigm for elucidation of mechanisms mediating antidepressant treatment resistance.
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ItemBeta adrenergic blockade reduces utilitarian judgement.(Elsevier BV, 2013-02)Noradrenergic pathways are involved in mediating the central and peripheral effects of physiological arousal. The aim of the present study was to investigate the role of noradrenergic transmission in moral decision-making. We studied the effects in healthy volunteers of propranolol (a noradrenergic beta-adrenoceptor antagonist) on moral judgement in a set of moral dilemmas pitting utilitarian outcomes (e.g., saving five lives) against highly aversive harmful actions (e.g., killing an innocent person) in a double-blind, placebo-controlled, parallel group design. Propranolol (40 mg orally) significantly reduced heart rate, but had no effect on self-reported mood. Importantly, propranolol made participants more likely to judge harmful actions as morally unacceptable, but only in dilemmas where harms were 'up close and personal'. In addition, longer response times for such personal dilemmas were only found for the placebo group. Finally, judgments in personal dilemmas by the propranolol group were more decisive. These findings indicate that noradrenergic pathways play a role in responses to moral dilemmas, in line with recent work implicating emotion in moral decision-making. However, contrary to current theorising, these findings also suggest that aversion to harming is not driven by emotional arousal. Our findings are also of significant practical interest given that propranolol is a widely used drug in different settings, and is currently being considered as a potential treatment for post-traumatic stress disorder in military and rescue service personnel.
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ItemPharmacological management of unipolar depression(WILEY, 2013-05)Objective To be used in conjunction with ‘Psychological management of unipolar depression’ [Lampe et al. Acta Psychiatr Scand 2013;127(Suppl. 443):24–37] and ‘Lifestyle management of unipolar depression’ [Berk et al. Acta Psychiatr Scand 2013;127(Suppl. 443):38–54]. To provide clinically relevant recommendations for the use of pharmacological treatments in depression derived from a literature review. Method Using our previous Clinical Practice Guidelines [Malhi et al. Clinical practice recommendations for bipolar disorder. Acta Psychiatr Scand 2009;119(Suppl. 439):27–46] as a foundation, these clinician guidelines target key practical considerations when prescribing pharmacotherapy. A comprehensive review of the literature was conducted using electronic database searches (PubMed, MEDLINE), and the findings have been synthesized and integrated alongside clinical experience. Results The pharmacotherapy of depression is an iterative process that often results in partial and non‐response. Beyond the initiation of antidepressants, the options within widely used strategies, such as combining agents and switching between agents, are difficult to proscribe because of the paucity of pertinent research. However, there is some evidence for second‐line strategies, and a non‐prescriptive algorithm can be derived that is based broadly on principles rather than specific steps. Conclusion Depression is by its very nature a heterogeneous illness that is consequently difficult to treat. Invariably, situation‐specific factors often play a significant role and must be considered, especially in the case of partial and non‐response. Consulting with colleagues and trialling alternate treatment paradigms are essential strategies in the management of depression.
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ItemSystematic Review of the Effectiveness of Pharmacologic Interventions to Improve Quality of Life and Well-being in People With Dementia(ELSEVIER SCIENCE INC, 2013-02)OBJECTIVE: To review systematically, for the first time, the effectiveness of all pharmacologic interventions to improve quality of life and well-being in people with dementia. DESIGN: Systematic review and meta-analysis. METHODS: We systematically reviewed the 15 randomized controlled trials and one review that fitted predetermined criteria. We included studies that reported the outcomes quality of life, well-being, happiness, or pleasure. MEASUREMENTS: We rated the validity of studies using a checklist. We calculated mean differences between intervention and control groups at follow-up. RESULTS: None of the evaluated trials reported a significant benefit to quality of life or well-being for people with dementia when comparing those taking a drug or its comparator at follow-up (pooled weighted mean difference: 0.18 [95% confidence interval: -0.82 to 0.46]). CONCLUSION: We found no consistent evidence that any drug improves quality of life in people with dementia. We recommend that all dementia trials should include quality of life as an outcome, as this is important to patients, and cannot be presumed from improvements in cognition or other symptomatic outcomes, especially if the latter are small.
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ItemProfiles of psychosocial outcome after epilepsy surgery: The role of personality(WILEY-BLACKWELL, 2010-07)PURPOSE: We have previously found that the developmental time frame of epilepsy onset influences adult personality traits and subsequent adjustment to intractable seizures. In the same cohort of patients we now investigate the influence of these factors on psychosocial outcome after surgical treatment. METHODS: Fifty-seven adult patients with focal epilepsy were prospectively assessed before and after surgery. Measures of psychosocial outcome included mood, health-related quality of life (HRQOL), and psychosocial adjustment, collected longitudinally at 1-, 3-, and 12-months after surgery. RESULTS: Patients with high neuroticism and low extraversion were predisposed to greater depression after surgery. More than 70% of patients with high neuroticism also reported disrupted family dynamics and difficulties adjusting to seizure freedom. The latter was associated with changes in self-identity that increased over time. Patients with epilepsy onset before or during the self-defining period of adolescence reported the greatest perceived self-change after surgery that had positive effects for HRQOL. DISCUSSION: Psychosocial outcome after epilepsy surgery appears intrinsically linked to a change in self and a transition from chronically sick to well. The development of personality traits and self-identity in the context of habitual seizures can impact psychosocial outcome and the extent of self-change reported after surgery, and paradoxically, can concur more beneficial effects.