Tonic dopamine: opportunity costs and the control of response vigor

RATIONALE: Dopamine neurotransmission has long been known to exert a powerful influence over the vigor, strength, or rate of responding. However, there exists no clear understanding of the computational foundation for this effect; predominant accounts of dopamine's computational function focus on a role for phasic dopamine in controlling the discrete selection between different actions and have nothing to say about response vigor or indeed the free-operant tasks in which it is typically measured. OBJECTIVES: We seek to accommodate free-operant behavioral tasks within the realm of models of optimal control and thereby capture how dopaminergic and motivational manipulations affect response vigor. METHODS: We construct an average reward reinforcement learning model in which subjects choose both which action to perform and also the latency with which to perform it. Optimal control balances the costs of acting quickly against the benefits of getting reward earlier and thereby chooses a best response latency. RESULTS: In this framework, the long-run average rate of reward plays a key role as an opportunity cost and mediates motivational influences on rates and vigor of responding. We review evidence suggesting that the average reward rate is reported by tonic levels of dopamine putatively in the nucleus accumbens. CONCLUSIONS: Our extension of reinforcement learning models to free-operant tasks unites psychologically and computationally inspired ideas about the role of tonic dopamine in striatum, explaining from a normative point of view why higher levels of dopamine might be associated with more vigorous responding.     

Investigation of G72 (DAOA) expression in the human brain

Background

Systematic reviews based on efficacy trials are inconclusive about which second generation antipsychotic drug (SGA) should be preferred in normal clinical practice, and studies with longer duration and more pragmatic designs are called for. Effectiveness studies, also known as naturalistic, pragmatic, practical or real life studies, adhere to these principles as they aim to mimic daily clinical practice and have longer follow-up.

Objective

To review the head-to-head effectiveness of SGAs in the domains of global outcomes, symptoms of disease, and tolerability.

Methods

Searches were made in Embase, PubMED, and the Cochrane central register of controlled trials for effectiveness studies published from 1980 to 2008, week 1. Different combinations of the keywords antipsychotic*, neuroleptic* AND open, pragmatic, practical, naturalistic, real life, effectiveness, side effect*, unwanted effect*, tolera* AND compar* AND random* were used.

Results

Sixteen different reports of randomized head-to-head comparisons of SGA effectiveness were located. There were differences regarding sample sizes, inclusion criteria and follow-up periods, as well as sources of financial sponsorship. In acute-phase and first-episode patients no differences between the SGAs were disclosed regarding alleviating symptoms of disease. Olanzapine was associated with more weight gain and adverse effects on serum lipids. In the chronic phase patients olanzapine groups had longer time to discontinuation of treatment and better treatment adherence compared to other SGAs. The majority of studies found no differences between the SGAs in alleviating symptoms of psychosis in chronically ill patients. Olanzapine was associated with more metabolic adverse effects compared to the others SGAs. There were surprisingly few between-drug differences regarding side effects. First generation antipsychotics were associated with lower total mental health care costs in 2 of 3 studies on chronically ill patients, but were also associated with more extrapyramidal side effects compared to the SGAs in several studies.

Conclusion

In chronically ill patients olanzapine may have an advantage over other SGAs regarding longer time to treatment discontinuation and better drug adherence, but the drug is also associated with more metabolic side effects. More effectiveness studies on first-episode psychosis are needed.     

Complete remission of metastatic carcinoma of the prostate with bicalutamide withdrawal

An 83-year-old man was diagnosed with stage 4 prostate cancer with a Gleason score of 7 (3+4). His initial prostate-specific antigen (PSA) level was 965 ng/dL, and he demonstrated extensive metastatic disease of the thoracic spine. After an initial response to monthly leuprolide injections, his PSA level began to increase and bicalutamide was added. An initial decrease in his PSA level was observed; however, the level gradually rose to 212 ng/dL and bicalutamide was discontinued. Three months later, his PSA level was <0.05 ng/dL and has remained <1 ng/dL for the past 27 months. Bicalutamide withdrawal usually leads to transient remission, with PSA level dropping to approximately 50% of the initial level. The duration of the remission is usually limited to approximately 6 months. However, the sustained response that was observed in our patient suggests that a trial of androgen withdrawal, even in the setting of rising PSA levels, might be reasonable before initiating more toxic therapies.