Rethinking Schizophrenia, Part III

Rethinking Schizophrenia, Part III

Cognition, GABA, and the Quiet Role of D3

In the first two parts of this series, I argued that our understanding of schizophrenia has been shaped for too long by what is easiest to see. Hallucinations and delusions are obvious, disruptive, and often frightening, so they naturally became the primary targets of treatment. Over time, we built a system that equated stability with silence, fewer voices, fewer crises, fewer hospitalizations, and we called that success.

But stability has never been the same thing as recovery. What ultimately determines whether someone can work, live independently, sustain relationships, or participate meaningfully in their own care is not how quiet their symptoms are, but how well they can think. Cognition sits at the center of functional outcome in schizophrenia, yet it has remained largely untouched by our pharmacologic tools.

That realization didn’t come to me from journals alone. It came from years spent in corrections and on my city’s ACT team, sitting across from people whose charts told one story and whose lived experience told another. I watched clients whose hallucinations were reasonably controlled still struggle to organize their thoughts, sustain attention, or process information quickly enough to function in the real world. I also watched others who continued to hear voices manage housing, employment, and relationships because they retained enough cognitive clarity to adapt. Over time, the pattern became impossible to ignore. Cognition was doing the heavy lifting.

In Part II, I discussed emerging evidence suggesting that cognition may not be as fixed as we once believed. A systematic review and network meta-analysis by Olgiati and colleagues, pooling data from 14 randomized trials with more than 2,400 participants, found that lurasidone and xanomeline showed the clearest improvements in global cognition, while cariprazine and quetiapine demonstrated more targeted gains, particularly in attention (Olgiati et al., 2025). These findings were largely derived from post hoc analyses, but they hinted at something important: different pharmacologic mechanisms may influence different cognitive domains, independent of their effects on psychosis.

This third piece is where I want to slow the conversation down and ask why that might be. Specifically, I want to place those attentional signals, particularly those seen with cariprazine, into a broader neurobiological context by revisiting the GABA hypothesis of schizophrenia and examining the role dopamine, and especially the D3 receptor, may play in supporting cognitive circuitry.

What ultimately pushed me in this direction was not a fascination with receptor pharmacology, but what cognition actually looks like when it fails. In real-world settings, the most devastating impairment is often not the presence of unusual beliefs or perceptual disturbances, but the inability to sustain focus long enough to follow instructions, organize a plan, or respond flexibly to changing demands. When attention and processing speed are compromised, everything else begins to unravel. Appointments are missed, medications are taken inconsistently, therapy becomes difficult to engage in, and even basic safety awareness deteriorates. Cognition is not an abstract construct, it is the scaffolding that holds functional recovery together.

This is where the GABA hypothesis becomes clinically meaningful. Schizophrenia has long been associated with dysfunction of parvalbumin-positive GABA interneurons in the prefrontal cortex, cells that play a critical role in synchronizing neural firing and maintaining the oscillatory rhythms that allow information to be processed coherently (Barch & Ceaser, 2012; McCutcheon et al., 2023). When these interneurons fail to regulate timing, cortical networks lose their ability to coordinate efficiently. Thoughts fragment, attention drifts, and working memory collapses. Importantly, this is not simply a problem of insufficient inhibition. It is a failure of precision.

That distinction helps explain why decades of attempts to directly enhance GABA transmission have largely failed to improve cognition. Increasing tonic inhibition may quiet neural activity, but it does not restore timing and often worsens processing speed and executive function (Green et al., 2000; Bowie & Harvey, 2006). You cannot recreate a fast-spiking interneuron by turning up the volume on inhibition. Schizophrenia, at its cognitive core, is a disorder of network coordination.

Dopamine re-enters this picture not as the primary driver of psychosis, but as a critical support system for cortical circuitry. Mesocortical dopamine signaling helps stabilize interneuron firing and supports the oscillatory coherence required for attention and executive function. In schizophrenia, this dopaminergic support is often inefficient. While D2 antagonism can reduce psychotic symptoms, it does little to repair the underlying network dysfunction that drives cognitive impairment, and in some cases may further dampen already fragile cortical signaling.

This is where dopamine D3 receptors become relevant. D3 receptors are concentrated in mesocortical and limbic regions and function as modulators rather than blunt switches, fine-tuning dopaminergic tone in circuits involved in motivation, attention, and cognitive effort (Stahl, 2017). Cariprazine’s preferential binding to D3 receptors, combined with its partial agonist properties, positions it differently from traditional dopamine-blocking agents.

Rather than simply suppressing dopamine, it stabilizes signaling in a context-dependent manner, functionally antagonistic where dopamine is excessive and supportive where it is deficient.

From a GABA perspective, this matters because dopamine does not directly increase inhibition. Instead, it supports the conditions under which inhibitory timing can function effectively. The result is not sedation or global suppression, but improved signal-to-noise efficiency within cortical networks. Attention, which is exquisitely sensitive to timing and synchronization, becomes a logical domain in which to see early movement.

This framework aligns with what has been observed in the available data. In the Olgiati meta-analysis, cariprazine did not emerge as a compound with broad global cognitive effects. Instead, its signal was more specific, appearing most consistently in attentional domains. Post hoc analyses from cariprazine trials, including work presented by Cutler and colleagues and later by McIntyre and colleagues, demonstrated modest but reproducible improvements in focused and sustained attention despite cognition not being a primary or secondary endpoint in these studies (Cutler et al., 2016; McIntyre et al., 2019).

It is essential to be clear about what these findings represent. Cognition was not a primary or secondary endpoint in these trials. The studies were designed to assess psychotic symptoms, not cognitive change, and they were not powered to detect cognitive effects. These results were derived from post hoc exploratory analyses and should be interpreted accordingly. They are hypothesis generating, not confirmatory.

Still, dismissing them outright would miss their clinical relevance. In community psychiatry, forensic settings, and ACT teams, attention is not a trivial outcome. The ability to focus long enough to engage in treatment, process instructions accurately, and maintain consistent routines underlies nearly every aspect of functional recovery. Even small improvements in attentional control can alter a person’s trajectory in ways that symptom scales do not fully capture. Evidence based, nonpharmacologic interventions assume a baseline capacity to attend and think. Cognitive remediation programs such as CIRCuiTS and SocialVille use neuroplasticity-based training to strengthen attention, memory, and problem-solving (Wykes et al., 2018; Nahum et al., 2021), but participation in these programs presupposes that an individual can sustain focus, follow task demands, and tolerate cognitive effort in the first place. When attention is too fragmented, even the best-designed cognitive therapies remain out of reach. Notably, cognitive changes in these analyses were not tightly coupled with improvements in positive symptoms, reinforcing decades of evidence showing that cognition, rather than symptom severity, is the strongest predictor of real-world functioning in schizophrenia (Bowie & Harvey, 2006).

Cariprazine is not a cognitive treatment, and it should not be framed as one. Neither is quetiapine. None of our currently approved antipsychotics were developed with cognition as a primary target. But when viewed together, these findings contribute to a broader pattern. Xanomeline based compounds show emerging signals in global cognition. Lurasidone appears to exert broader cognitive effects than most second-generation antipsychotics. Cariprazine repeatedly shows a domain-specific signal in attention.

This does not represent the end of the story. It represents a shift in direction. For decades, schizophrenia treatment has optimized for symptom suppression while accepting cognitive impairment as an unavoidable consequence. The GABA hypothesis helps explain why cognition has been so resistant to treatment, and D3 biology offers one plausible route around that limitation. Cariprazine’s attentional signal is modest and preliminary, but for clinicians working in the trenches, even incremental progress matters. Attention is often the first cognitive door that must reopen before higher-order functioning can return.

If recovery is truly our goal, cognition can no longer remain a secondary concern. Our trials, outcome measures, and treatment paradigms must evolve to reflect what actually determines function in real life. We need studies designed with cognition as a primary endpoint, tools sensitive enough to detect meaningful change, and systems that recognize recovery as more than the absence of crisis.

In the earlier parts of this series, I argued that we need to rethink schizophrenia and re-engineer our goals. This piece adds another layer: understanding the circuitry well enough to know where leverage might actually exist. Cognition has spent decades riding quietly in the back seat of schizophrenia treatment. If we want real recovery, it is time to let it drive, and to build therapies that finally acknowledge how the brain actually works.

References

Barch, D. M., & Ceaser, A. (2012). Cognition in schizophrenia: Core psychological and neural mechanisms. Trends in Cognitive Sciences, 16(1), 27–34.

Bowie, C. R., & Harvey, P. D. (2006). Cognitive deficits and functional outcome in schizophrenia. Neuropsychiatric Disease and Treatment, 2(4), 531–536.

Cutler, A. J., Durgam, S., Lu, K., Laszlovszky, I., & Earley, W. (2016). Efficacy of cariprazine on negative, cognitive, and social function symptoms in schizophrenia: Post hoc analysis of a randomized, controlled trial. Poster presented at the 169th Annual Meeting of the American Psychiatric Association, Atlanta, GA.

Green, M. F., Kern, R. S., Braff, D. L., & Mintz, J. (2000). Neurocognitive deficits and functional outcome in schizophrenia: Are we measuring the “right stuff”? Schizophrenia Bulletin, 26(1), 119–136. https://doi.org/10.1093/oxfordjournals.schbul.a033430

McCutcheon, R. A., Keefe, R. S. E., & McGuire, P. K. (2023). Cognitive impairment in schizophrenia: Aetiology, pathophysiology, and treatment. Molecular Psychiatry, 28(5), 1902–1918.

McIntyre, R. S., Daniel, D. G., Earley, W., Patel, M., Laszlovszky, I., & Wesnes, K. A. (2019). Effects of cariprazine on attentional processes in patients with schizophrenia: Post hoc analysis from a randomized, controlled phase III study. Poster presented at the 172nd Annual Meeting of the American Psychiatric Association, San Francisco, CA.

Olgiati, P., McIntyre, R. S., Huhn, M., et al. (2025). Impact of selected second- and third-generation antipsychotics on cognitive dysfunction in schizophrenia-spectrum disorders: A systematic review and network meta-analysis. International Clinical Psychopharmacology. Advance online publication.

Stahl, S. M. (2017). Drugs for psychosis and mood: Unique actions at D3, D2, and D1 dopamine receptor subtypes. CNS Spectrums, 22(5), 375–384.

Wykes, T., Huddy, V., Cellard, C., McGurk, S. R., & Czobor, P. (2011). A meta-analysis of cognitive remediation for schizophrenia: Methodology and effect sizes. American Journal of Psychiatry, 168(5), 472–485.

Wykes, T., Ramsay, R., Williams, C., et al. (2018). Implementation of cognitive remediation in early intervention services (CIRCuiTS): A randomized controlled trial. Trials, 19(1), 183.

Nahum, M., Fisher, M., Loewy, R., et al. (2021). Online social cognition training in schizophrenia: A double-blind, randomized, controlled multi-site trial. Schizophrenia Bulletin, 47, 108–117.

‍