Schizophrenia: Overview and Dopamine Dysfunction

Anissa Abi-Dargham, MD

Division of Translational Imaging, Department of Psychiatry, Columbia University and New York State Psychiatric Institute, New York


Schizophrenia is a chronic, often disabling illness that affects approximately 24 million people worldwide.1 Although the first priority of ongoing treatment is to delay relapse, the ultimate goal is complete recovery, with recent research focusing on improving patients’ quality of life and helping them achieve functional recovery.2

Unfortunately, while the majority of first-episode schizophrenia patients respond well to initial antipsychotic treatment, fewer than 1 in 5 will maintain recovery over 5 years, and most will experience at least 1 relapse.3 With each relapse, the illness becomes more resistant to treatment and patients have more difficulty regaining previous levels of functioning, resulting in a lower quality of life and a higher socioeconomic burden.4 For example, patients with schizophrenia who relapse have approximately 4 times the cost of care of those who do not relapse, primarily due to receiving inpatient care.5

Positive symptoms of the disorder include hallucinations, delusions, and thought or movement disorders, while negative and cognitive symptoms consist of blunted affect, anhedonia, asociality, avolition, alogia, inattention, poor executive functioning, and problems with working memory. In managing these symptoms, current antipsychotics only address the positive psychotic symptoms of schizophrenia, but the disabling negative and cognitive symptoms can persist. Antipsychotics are primarily dopamine D2 antagonists or partial agonists, meaning that they interfere with D2 stimulation, reducing the dopamine hyperactivity that results in the positive symptoms of schizophrenia. To better understand this disorder, it is essential to understand the role of dopamine in the symptoms and treatment of schizophrenia.

Dopamine Dysfunction

Information processing and motivational behavior are mediated by cortico-striatal-pallidal-thalamo-cortical loops. These circuits project glutamatergic neurons from cortical regions, such as the orbitofrontal, dorsolateral, and sensorimotor cortices, to the striatum. The striatum sends inhibitory GABAergic–containing projections to the pallidum, which itself projects GABAergic neurons to the thalamus. The thalamus then sends glutamatergic projections back to the cortex (AV 1). These loops are modulated by dopaminergic input from ventral tegmentum to the striatum, and dopamine dysfunction at this level has been shown to lead to the positive symptoms of schizophrenia.

AV 1. Cortico-striatal-pallidal-thalamo-cortical Loops Are Modulated by Dopaminergic Input (02:44)


Dopamine dysregulation begins early in the disease course and can be detected during the prodromal phases of schizophrenia. For example, the dopamine synthesis rate is elevated in patients with prodromal symptoms of schizophrenia, and this elevation rate is related to the severity of prodromal symptoms and to the severity of cognitive deficits.6 The prodromal phase is also associated with elevated cerebral blood volume (CBV), which is an index of increased neural activity and thought to be an index of excess glutamatergic transmission in the ventral hippocampus. Both increased dopamine synthesis rate and increased CBV in the hippocampus have been shown to predict conversion to schizophrenia.7 Preclinical animal models suggest that these observations may be linked because hippocampal glutamatergic overdrive may disinhibit dopamine midbrain cell–firing activity.


In the striatum, dopamine is modulated in 3 areas: the ventral limbic (processes emotional information), associative (processes cognitive information), and regions that process sensorimotor information (see AV 1). Striatal dopamine alterations in schizophrenia include increased dopamine synthesis, release, and D2 receptor density.8–14 Excess presynaptic dopamine in the dorsal striatum or abnormal postsynaptic D2 receptor sensitivity has been shown to relate to the positive symptoms of psychosis (AV 2).12,15 Additionally, excess striatal dopamine release predicts the therapeutic response of psychotic symptoms to antipsychotics.12 Thus, modulating striatal dopamine via D2 receptor-blockade has been shown to improve positive symptoms for patients with schizophrenia.12

AV 2. Excess Presynaptic Dopamine in the Dorsal Striatum Relates to the Positive Symptoms of Psychosis (00:52)

Reprinted with permission from Thompson et al15
Solid line = least-squares fit for dual diagnosis patients
Dashed line = no change in PANSS score

Dopamine levels in the ventral limbic striatum are elevated in schizophrenia, although not to the extent seen in the associative striatum. However, in relation to schizophrenia symptoms, low dopamine release in this area directly impacts the severity of negative symptoms (ie, the lower the dopamine levels, the more negative symptoms).13 A dopamine deficit in the cortical regions, as well as alterations in glutamate and GABA in the cortical regions (which can create an imbalance in midbrain dopaminergic inhibition and excitation), may contribute to negative symptoms as well as to cognitive symptoms in schizophrenia. Because antipsychotics currently act via D2 receptor-blockade, they are unlikely to improve negative or cognitive symptoms, which may be related to low dopamine and low dopaminergic stimulation of cortical dopamine receptors, respectively. Therefore, antipsychotic agents with novel mechanisms of action are needed to treat the full spectrum of schizophrenia symptoms.


Although dopamine has a role in the pathophysiology of schizophrenia, dopamine dysfunction does not adequately describe the etiology of all aspects of schizophrenia, especially the underlying pathology of negative and cognitive symptoms. The field needs a better understanding of brain alterations in schizophrenia that affect other neurobiologic systems, which can lead to alternative treatment targets to better and more comprehensively address all facets of schizophrenia.

Clinical Points

  • The goal of schizophrenia treatment is improving patients’ quality of life and helping them to achieve functional recovery
  • Dopamine dysfunction helps to explain the positive symptoms of schizophrenia
  • More treatments are needed that address the negative and cognitive symptoms, in addition to the positive symptoms, of schizophrenia
  • Unlike current antipsychotic agents, new treatments that address the negative and cognitive symptoms of schizophrenia are unlikely to act by primarily altering dopaminergic dysfunction


CBV = cerebral blood volume
D = dopamine receptor
GABA = γ-aminobutyric acid
PANSS = Positive and Negative Syndrome Scale


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Schizophrenia: Overview and Dopamine Dysfunction