Schizophrenia: It’s Not Just About Dopamine

Psychiatric TimesVol 32 No 6
Volume 32
Issue 6

Physicians recognize many features of schizophrenia, but one neglected area is the common symptom of a poor self-other boundary-in fact, this has also been neglected as a criterion for the DSM.

Physicians recognize many features of schizophrenia, including positive and negative symptoms, social/occupational effects, cognitive problems, comorbid substance abuse disorders, and mood changes. However, one neglected area is the common symptom of a poor self-other boundary-in fact, this has also been neglected as a criterion for DSM, despite the fact that it is a common symptom of schizophrenia and that there is a vast literature on the topic.1

In his talk, “Beyond Dopamine: the Evolving Therapeutics of Schizophrenia,” at APA 2015, Henry A. Nasrallah, MD, Chair of the Department of Neurology and Psychiatry at the St Louis University School of Medicine, noted that 95% of patients with a first episode of psychosis have had contact with the health care system before the first psychotic episode. This makes recognition of prodromal symptoms and risk factors especially important.

[[{"type":"media","view_mode":"media_crop","fid":"38663","attributes":{"alt":"dopamine, © Christopher Meade/","class":"media-image media-image-right","id":"media_crop_612741986218","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"3867","media_crop_rotate":"0","media_crop_scale_h":"178","media_crop_scale_w":"150","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"float: right;","title":"© Christopher Meade/","typeof":"foaf:Image"}}]]Schizophrenia needs to be recognized, according to Nasrallah, as a disorder with a neurodevelopmental basis that is characterized by progressive brain atrophy. With increased psychotic episodes, the ventricular system of persons with schizophrenia enlarges. “Why can’t we do something?” asked Nasrallah.

In addition, gray matter is lost.2 “The parietal lobe, temporal lobe, and prefrontal cortex take a huge loss,” said Nasrallah. There is also a loss of dendritic spines,3 the substrates of cognition and memory.

“But we focus on dopamine,” Nasrallah noted, despite the evidence for neurodegeneration in schizophrenia.

In addition to the loss of global gray matter and dendritic spines, Nasrallah stated that glial cells die in schizophrenia-perhaps accounting for gray matter deficits rather than neuronal loss. “When the glial cells die during a psychotic episode, the neurons become helpless,” observed Nasrallah. Effects on glia in schizophrenia remains a topic of much research, although controversy about the exact nature of glial effects might remain.4

To add further insult to injury, trophic factors-from which neu-rons derive their support and ability to differentiate, grow axons, and survive-are also affected, such as brain-derived neurotrophic factor.5

Researchers have conducted numerous studies of neurogenesis and antipsychotics, finding that atypical antipsychotics increase neurogenesis, but that haloperidol may be neurotoxic.6,7 In addition, atypical antipsychotics appear to boost levels of neurotrophins in the brains of persons with schizophrenia.8

Given this evidence for numerous other processes, can the neurochemical model of schizophrenia go beyond dopamine? Nasrallah questioned the focus on that sole neuro-transmitter system, asking “why aren’t we using GABA agonists in conjunction with the dopamine antagonists?” He also mentioned that the antihypertensive agent nitroprusside could be effective for treating schizophrenia.9 Oxytocin might also hold potential.

Nasrallah believes that therapeutic approaches should concentrate on the neurodevelopmental dimension of schizophrenia. Prevention might also help, for example, protect pregnant women from the risk factors associated with increased schizophrenia risk-such as maternal infections, toxoplasmosis, and gestational diabetes-and ensuring safe deliveries.

In addition, Nasrallah suggested that it might be possible to prevent neurodegeneration and minimize the risk of psychosis through the early use of long-acting atypical antipsychotics. In general, he advocated the urgent need for “therapeutic approaches and strategies that go beyond what we are doing now.”


This article was originally posted on May 22, 2015 and has since been updated.


1. Pauly K, Kircher T, Weber J, et al. Self-concept, emotion and memory performance in schizophrenia. Psychiatry Res. 2011;186:11-17.

2. Thompson PM, Vidal C, Giedd JN, et al. Mapping adolescent brain change reveals dynamic wave of accelerated gray matter loss in very early-onset schizophrenia. Proc Natl Acad Sci U S A. 2001;98:11650-11655.

3. Konopaske GT, Lange N, Coyle JT, Benes FM. Prefrontal cortical dendritic spine pathology in schizophrenia and bipolar disorder. JAMA Psychiatry. 2014;71:1323-1331.

4. Schnieder TP, Dwork AJ. Searching for neuropathology: gliosis in schizophrenia. Biol Psychiatry. 2011;69:134-139.

5. Buckley PF, Pillai A, Howell KR. Brain-derived neurotrophic factor: findings in schizophrenia. Curr Opin Psychiatry. 2011;24:122-127.

6. Benninghooff J, Grunze H, Schindler C, et al. Ziprasidone-not haloperidol-induces more de-novo neurogenesis of adult neural stem cells derived from murine hippocampus. Pharmacopsychiatry. 2013;46:10-15.

7. Martins MR, Petronilho FC, Gomes KM, et al. Antipsychotic-induced oxidative stress in rat brain. Neurotox Res. 2008;13:63-69.

8. Rizos E, Papathanasiou MA, Michalopoulou PG, et al. A longitudinal study of alterations of hippocampal volumes and serum BDNF levels in association to atypical antipsychotics in a sample of first-episode patients with schizophrenia. PLoS One. 2014;9:e87997.

9. Hallak JE, Maia-de-Oliveira JP, Abrao J, et al. Rapid improvement of acute schizophrenia symptoms after intravenous sodium nitroprusside: a randomized, double-blind, placebo-controlled trial. JAMA Psychiatry. 2013;70:668-676.

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