Neural Basis for the Ability of Atypical Antipsychotic Drugs to Improve Cognition in Schizophrenia

Cognitive impairments are considered to largely affect functional outcome in patients with schizophrenia, other psychotic illnesses, or mood disorders. Specifically, there is much attention to the role of psychotropic compounds acting on serotonin (5-HT) receptors in ameliorating cognitive deficits of schizophrenia. It is noteworthy that atypical antipsychotic drugs (AAPDs), e.g., clozapine, melperone, risperidone, olanzapine, quetiapine, aripiprazole, perospirone, blonanserin, and lurasidone, have variable affinities for these receptors. Among the 5-HT receptor subtypes, the 5-HT1A receptor is attracting particular interests as a potential target for enhancing cognition, based on preclinical and clinical evidence. The neural network underlying the ability of 5-HT1A agonists to treat cognitive impairments of schizophrenia likely includes dopamine, glutamate, and gamma-aminobutyric acid neurons. A novel strategy for cognitive enhancement in psychosis may be benefited by focusing on energy metabolism in the brain. In this context, lactate plays a major role, and has been shown to protect neurons against oxidative and other stressors. In particular, our data indicate chronic treatment with tandospirone, a partial 5-HT1A agonist, recover stress-induced lactate production in the prefrontal cortex of a rat model of schizophrenia. Recent advances of electrophysiological measures, e.g., event-related potentials, and their imaging have provided insights into facilitative effects on cognition of some AAPDs acting directly or indirectly on 5-HT1A receptors. These findings are expected to promote the development of novel therapeutics for the improvement of functional outcome in people with schizophrenia.

This paper provides a hypothesis regarding the neural basis for the ability of AAPDs to improve cognition. This theoretical issue is important from the perspective of the development of therapeutics for enhancing long-term outcome in patients with schizophrenia.

DO AAPDs ENHANCE COGNITION IN SCHIZOPHRENIA?
Typical antipsychotic drugs, such as perphenazine, have been reported to show some cognitive benefits in schizophrenia with a small effect size, as reported in the CATIE trial (Keefe et al., 2007). Importantly, Woodward et al. (2005) report an advantage of AAPDs over TAPDs in terms of enhancing cognition with a moderate effect size both in controlled and uncontrolled trials. However, there have been challenges to the pro-cognitive efficacy of AAPDs. For example, improvement of verbal memory by treatment with risperidone or olanzapine has been suggested to be no better than that of practice effect (or more precisely, test-retest effect) in normal controls (Goldberg et al., 2007). However, it may be premature to conclude that way, since no data were presented in that study (Goldberg et al., 2007) as to whether schizophrenia patients not receiving these AAPDs would have elicited the same degree of improvement as that in treated patients (Sumiyoshi, 2013).
One of the suggestions for this debate comes from the ability of lurasidone to dose-dependently improve cognitive functions, as measured by a computer-based test battery (Maruff et al., 2009), in a placebo-controlled double-blind study (Harvey et al., 2013;Sumiyoshi, 2013). This result provides a support for the ability of some AAPDs to enhance cognition in patients with schizophrenia, which is independent of a practice effect.

Frontiers in Behavioral Neuroscience www.frontiersin.org
Another issue is what percentage of patients can be treated with a clinically meaningful degree. It is reported that a larger than 0.5 SD improvement in cognition substantially improves quality of life for patients (Norman et al., 2003). Accordingly, treatment with clozapine produced a significantly larger proportion of patients showing a larger than 0.5 SD improvement in letter fluency that predicts work outcome (Sumiyoshi and Meltzer, in preparation). Again, these findings provide a support for the proposition that AAPDs are superior over TAPDs for enhancing cognition.
In spite of these lines of evidence, cognitive benefits of AAPDs have been questioned, as noted above. One of the main reasons may be that the neural mechanisms for it have not been fully elucidated. Therefore, the following sections address this issue from the perspective of electrophysiological imaging, neural network, and energy metabolism. Figure 1 illustrates a rationale for electrophysiological approach toward cognitive assessment. The combination of neuropsychological and electrophysiological methods, e.g., event-related potentials (ERPs), may be beneficial for the understanding of mechanisms of cognitive enhancement, rational choice of psychotropic drugs, and prediction of functional outcome.

ELECTROPHYSIOLOGICAL IMAGING
Specifically, we reported the effect of olanzapine on cognition and QOL, as well as P300, a component of ERPs, in patients with schizophrenia (Higuchi et al., 2008). P300 has been used as a marker of attentive cognitive processes. Figure 2 (right) demonstrates P300 waveforms. At baseline, P300 amplitudes of patients were diminished compared to those of control subjects. After 6 month treatment with olanzapine, P300 amplitudes were increased, as were scores of verbal memory and quality of life (Figure 2, left).
We subsequently evaluated the effect of olanzapine on P300 current source density in discrete brain areas (Higuchi et al., 2008) (Figure 3). At baseline, P300 current density in the left superior temporal gyrus (STG) was decreased in patients. Olanzapine increased P300 current density in the left STG, but not other regions, such as the prefrontal cortex (PFC). In fact, this left-dominant pattern of P300 current density is similar to that for control subjects. These observations provide the first evidence that AAPDs ameliorate neurocognitive disturbances by correcting three-dimensional distribution of electrophysiological activity (Sumiyoshi et al., , 2009Higuchi et al., 2008).
An important aspect of this study was the correlation between the change in P300 current density and cognition or functional outcome. In fact, there was a significant positive correlation between improvement of verbal memory and enhancement of P300 current density in the left STG (Figure 4, right). Also, the change in the Quality of Life score (Heinrichs et al., 1984) was significantly correlated with enhancement of P300 current density in the left PFC (Figure 4, left). These results indicate that the change of regional electrophysiological activities in response to treatment can predict enhancement of cognitive and functional outcomes (Higuchi et al., 2008;Sumiyoshi et al., 2009Sumiyoshi et al., , 2011. We also investigated the effect of perospirone on P300 current density (Sumiyoshi et al., 2009). Perospirone is one of the AAPDs marketed in Japan, and has high affinity for 5-HT 1A receptors (Araki et al., 2006;Sumiyoshi et al., 2009;Higuchi et al., 2013). Unlike the case for olanzapine, perospirone enhanced P300 current density in the left PFC in patients with schizophrenia ( Figure 5). This change was correlated with improvement of cognitive function relevant to daily living skills (Sumiyoshi et al., 2009).
These observations are consistent with our previous report that 5-HT 1A receptor density is increased in the left PFC from subjects with schizophrenia (Sumiyoshi et al., 1996). The upregulation of 5-HT 1A receptors is hypothesized to reflect a compensatory reaction to diminished neurotransmission through FIGURE 1 | Electrophysiological approach toward cognitive assessment in schizophrenia. This strategy is expected to facilitate (1) elucidation of mechanisms of cognitive enhancement, (2) rational choice of psychotropic drugs, and (3) prediction of functional outcome.
FIGURE 2 | P300 waveforms in response to olanzapine treatment (right). P300 waveforms were averaged for 16 subjects per group. Black lines represent P300 activity for control subjects. Blue lines show P300 for patients at baseline, whose amplitudes are diminished compared to control subjects. After 6 month treatment with olanzapine, P300 amplitudes were increased, as indicated by redlines. Scores of verbal memory and quality of life were also increased by olanzapine (inset). Bars represent mean + SE.
FIGURE 3 | Effect of olanzapine on P300 current density, evaluated by the LORETA methods, in patients with schizophrenia. At baseline, P300 current density in the left superior temporal gyrus was decreased.
Olanzapine increased P300 current density in this brain region (circled), and this pattern of three-dimensional configuration was similar to that in control subjects.
Frontiers in Behavioral Neuroscience www.frontiersin.org  Left, grand average of ERP waveforms before (black lines) and after (red lines) treatment with perospirone in patients with schizophrenia. Right, 6 months treatment with perospirone enhanced P300 current density, evaluated by the sLORETA method, in the left superior frontal gyrus. Perospirone also improved social cognition, the degree of which was correlated with P300 activity in the frontal brain regions (see text).

NEURAL NETWORK MEDIATING COGNITIVE ENHANCEMENT OF AAPDs
As discussed, 5-HT 1A receptor agonism has been suggested to enhance cognition [see also Sumiyoshi et al. (2008)]. In fact, the addition of tandospirone, a 5-HT 1A partial agonist, improved executive function and verbal memory in patients treated with TAPDs (Sumiyoshi et al., 2001a,b) (Figure 6). Data from these clinical trials suggest 5-HT 1A agonists enhance some of the key cognitive domains, including those associated with frontal cortical function. Figure 7 illustrates a neural network providing a possible basis for the ability of tandospirone and AAPDs acting on 5-HT 1A receptors to enhance cognition. Systemic administration of 5-HT 1A agonists has been shown to selectively stimulate 5-HT 1A receptors located on gamma-aminobutyric acid (GABA) interneurons in the PFC (Llado-Pelfort et al., 2011;Sumiyoshi and Higuchi, 2013). This diminishes the activity of GABA neurons, leading to disinhibition of Glu neurons. This may explain the ability of AAPDs to augment DA release in the PFC , a putative mechanism for the ability of AAPDs to enhance cognition, in a 5-HT 1A receptor-dependent manner (Diaz-Mataix et al., 2005;Bortolozzi et al., 2010). These neural events may explain the ability of augmentation therapy with tandospirone to restore mismatch negativity amplitudes (Higuchi et al., 2010), an electrophysiological measure of glutamatergic activity that is diminished in schizophrenia (Javitt et al., 2008). Other possible  Sumiyoshi and Higuchi, 2013). This also leads to activation of meso-cortical dopamine neurons. For example, administration of clozapine, a 5-HT 1A agonist, increases extracellular DA concentrations in the prefrontal cortex in mice, but it does not occur in mutant mice lacking 5-HT 1A receptors (Bortolozzi et al., 2010). These neural events may explain the ability of augmentation therapy with tandospirone to restore mismatch negativity amplitudes (Higuchi et al., 2010), an electrophysiological measure of glutamatergic activity that is diminished in schizophrenia. VTA, ventral tegmental area.

ROLE FOR ENERGY METABOLISM
Traditionally, energy supply into the brain has been considered to depend on glucose. However, recent research suggests lactate plays a significant role in energy production both in the aerobic and anaerobic conditions, irrespective of the presence of glucose (Wyss et al., 2011;Uehara and Sumiyoshi, 2013). The lactate-dependent energy metabolism has been associated with glutamatergic activity (Uehara et al., 2008). Specifically, glutamatergic transmissions enhance lactate production, which is mediated by N -methyl-d-aspartate (NMDA) receptors and glutamate transporters, as well as astrocytes (Uehara et al., 2008;Uehara and Sumiyoshi, 2013). Recently, lactate has been shown to exert neuroprotective effects (Wyss et al., 2011). These lines of evidence prompted us to use lactate metabolism as a biological basis for the effect of pro-cognitive drugs.
Measurement of lactate in the extracellular space can provide real-time information on its production (Uehara et al., 2008). Lactate metabolism was hypothesized to reflect energy supply in the brain areas crucial for cognitive functions, e.g., PFC. Figure 8 describes the effect of tandospirone on extracellular lactate concentrations in a rat model of schizophrenia (Uehara et al., 2012). At the neonatal stage (postnatal days 7-10), rats were transiently administered MK-801, an antagonist at the NMDA receptor. In this experiment, these model rats showed suppression of the stressinduced increment of lactate levels in the PFC, suggesting impaired energy metabolism. This suppression in the model rats was inhibited by chronic treatment with tandospirone (once daily for 14 days before the measurement of lactate levels) (Uehara et al., 2012). These results are consistent with clinical observations that 5-HT 1A agonists, such as tandospirone and buspirone, ameliorate cognitive impairment related to PFC function (Sumiyoshi et al., 2001a(Sumiyoshi et al., ,b, 2007.
Another issue to be considered in the development of promising agents is the assessment of functional outcome, in addition to neurocognition (neuropsychological performance, or "primary measures"). In this context, intermediate functional measures, or "co-primary measures," have attracted interest as a target for therapeutic intervention (Sumiyoshi and Sumiyoshi, in press). For example, a greater sensitivity to treatment has been reported for co-primary measures compared to primary measures in a clinical trial of lurasidone and ziprasidone (Harvey et al., 2011). Therefore, intermediate functional measures (co-primary measures) deserve more attention in the development of novel pharmacotherapy for schizophrenia and related illnesses.
In conclusion, AAPDs have been shown to enhance cognition in a clinically meaningful manner. The mechanisms for it may include several modes of action and neural networks, which requires further explorations.

Frontiers in Behavioral Neuroscience
www.frontiersin.org