Schizophrenia Research Forum - A Catalyst for Creative Thinking

Antipsychotics Enhance Reward Signals, With Mixed Results

Updated 6 September 2012 to reflect a correction about the study by Mathews et al. The researchers studied healthy volunteers, not medication-naive people with schizophrenia.

23 August 2012. Antipsychotics elevate signals in the brain’s reward pathways, with wanted and unwanted effects, according to two new brain imaging studies published online August 6 in Archives of General Psychiatry. One study, led by Birte Glenthoj at Copenhagen University Hospital, Denmark, reports that amisulpride reversed abnormally low activity in the striatum found in schizophrenia, and that this correlated with symptom improvement. The second study, led by Deanna Barch of Washington University in St. Louis, Missouri, detected multiple eating-related changes upon taking olanzapine, an antipsychotic known for inducing swift and profound weight gain. The studies suggest that reward abnormalities may be corrected—and introduced by—antipsychotic treatment.

Consisting of subcortical regions like the striatum and higher areas like prefrontal cortex, reward pathways mediate the anticipation of, or pleasure at, receiving rewards like food or money. These regions rely on dopaminergic inputs to work, with dopamine release associated with the experience of reward and with anticipation of reward. Phasic dopamine release highlights prediction errors—the difference between what is expected and what actually happens (Schultz and Dickinson, 2000). By flagging the unexpected, these signals are thought to contribute to learning about important outcomes, and to the drive to achieve them.

The overactive dopamine signaling found in schizophrenia has raised the possibility that abnormalities in reward processing mediate the disorders’ symptoms. For example, according to an “aberrant salience hypothesis,” wayward dopamine signals tag innocuous stimuli as important, giving rise to delusions and hallucinations (Kapur, 2003). Likewise, attenuated prediction errors have recently been proposed to spur auditory hallucinations (Nazimek et al., 2012). Negative symptoms, including deficits in motivation, might also have their roots in an impaired ability to learn from rewards (Gold et al., 2012; see also SRF Forum Discussion). Consistent with these ideas, brain imaging of unmedicated people with schizophrenia finds blunted activity in the ventral striatum (consisting of the nucleus accumbens and the olfactory tubercle), a region central to reward processing (e.g., Juckel et al., 2006).

But how do these reward regions respond to antipsychotics? The new studies explore this question through functional magnetic resonance imaging (fMRI) to compare snapshots of the brain before and after taking antipsychotics, and examined blood oxygen level-dependent (BOLD) signals while participants waited for a reward, or while they experienced reward.

Follow the money
In the first study, Glenthoj’s group built on their previous results finding attenuated activity in the ventral striatum during reward anticipation in schizophrenia (Nielsen et al., 2012). A subset of these participants with schizophrenia completed the new study (n = 23), which required a six-week course of amisulpride. The researchers chose amisulpride because of its relatively selective D2/D3 receptor blockade. Six weeks of amisulpride treatment was associated with improvements in PANSS scores, functioning, and depression. Twenty-four matched controls were also scanned at two time points, six weeks apart, but without treatment.

First author Mette Odegaard Nielsen and colleagues used a monetary incentive delay task during scanning, in which the participants tried to win money. When shown a visual cue that indicated they might win money, they tried to respond as quickly as possible with a key press; if they responded in time, they were notified of their win (seven euros), but if they were too late, they made nothing. Likewise, when cued that they might lose money, a quick enough response would avert this loss, but a slow one would dock them seven euros.

At baseline, brain activity in the ventral striatum increased while participants waited to find out whether they were quick enough to earn a reward. This increase was meager, however, in the schizophrenia group compared to controls. In contrast, at follow-up the schizophrenia group achieved a similar level of ventral striatum activity, due to both an increase on their part and a decrease in the control group. This suggests that antipsychotic treatment normalized the brain’s responses to reward, and the change may be linked to symptoms: within the schizophrenia group, the researchers found a direct correlation between the change in right ventral striatum signal and positive symptom improvement (r = 0.54, p = 0.008).

It’s unclear whether amisulpride directly shapes reward signals, or whether the decrease in psychotic symptoms it ushers in allows better reward learning. The authors suggest the former, based on an inverse correlation between dopamine synthesis and activity in ventral striatum recently reported in healthy controls (Schlagenhauf et al., 2012). In schizophrenia, the researchers propose that overactive dopamine signaling drowns out the phasic, information-rich dopamine signals in which the ventral striatum is interested. Amisulpride would boost these signals by quieting down the noisy dopamine inputs, thus helping the ventral striatum to encode the pertinent reward information.

Overboard reward?
The second study searched for neural correlates of the troubling weight gain induced by atypical antipsychotics, especially with olanzapine. Olanzapine works on an array of targets, including dopaminergic, serotonergic, and histaminergic receptors, and these have been associated with weight gain (Roerig et al., 2011). Because olanzapine’s diverse receptor actions may converge on the brain’s reward regions, Barch’s team explored how responsive these regions were to reward before and after a brief course of olanzapine.

First author Jose Mathews and colleagues studied 19 healthy volunteers, none of whom were obese. They were scanned while expecting food (after a visual cue signaled whether they would receive chocolate milk, tomato juice, or water) and when they received it (through a small tube held in their mouths). The researchers followed brain activity in regions implicated in taste and eating in healthy people at baseline and after seven days on olanzapine. During this time, the participants gained an average of 1.1 kg, reported eating more, and consumed 35 percent more for breakfast, which was offered immediately after scanning.

Gains of the BOLD sort were detected in the brain as well. After seven days of olanzapine, the researchers detected elevated activity to cues predicting reward, in this case chocolate milk and tomato juice, but not to water. This occurred in the inferior frontal cortex, anterior cingulate cortex, and the striatum, and is consistent with enhanced responses to food cues found in obesity studies (e.g., Stice et al., 2008). During consumption, enhanced activity also emerged in the dorsal striatum in response to the rewarding milk or juice. This contrasts with the blunted activity in this region found in obese people—a deficit that may drive them to eat more in search of a pleasurable response to food. The authors suggest that what they found could be an early phase, and that a similar decrease could unfold with time.

One notable decrease in brain activity emerged relative to baseline: reduced activity in the lateral orbital frontal cortex during milk or juice consumption. This region is thought to put the brakes on eating (Gearhardt et al., 2011), and the diminished activity here may permit the enhanced food responses to run unchecked. The authors note that, “[The] multifactorial interplay between the pharmacological effects of olanzapine, homeostatic food intake mechanisms (central and peripheral), and the taste reward system likely results in weight gain.” The complicated picture of antipsychotic action offered by both studies, especially when multiple neurotransmitter systems are involved, highlights the importance of understanding the full spectrum of their effects in the brain in order to find more useful drugs in the future.—Michele Solis.

Nielsen MO, Rostrup E, Wulff S, Bak N, Broberg BV, Lublin H, Kapur S, Glenthoj B. Improvement of Brain Reward Abnormalities by Antipsychotic Monotherapy in Schizophrenia. Arch Gen Psychiatry. 2012 Aug 6:1-10. Abstract

Mathews J, Newcomer JW, Mathews JR, Fales CL, Pierce KJ, Akers BK, Marcu I, Barch DM. Neural Correlates of Weight Gain With Olanzapine. Arch Gen Psychiatry. 2012 Aug 6:1-11. Abstract