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High Dopamine Levels in People With Evidence of Prodromal Schizophrenia

25 January 2009. It has long been recognized that dopamine dysregulation may contribute to symptoms of schizophrenia. What is not clear is how this abnormality affects schizophrenia onset and symptoms. Oliver Howes and colleagues at the Institute of Psychiatry at King’s College London have published a study in the January Archives of General Psychiatry that examined brain dopamine function in people at high risk of schizophrenia who show early signs of developing the illness. Patients with prodromal signs of schizophrenia showed dopamine "overactivity" in the striatum relative to control subjects, as did patients with diagnosed schizophrenia. Within the potentially prodromal group dopamine overactivity was related to the severity of prodromal symptoms and impairment in verbal fluency.

Increases in striatal dopamine activity are believed to underlie schizophrenia psychotic, or “positive,” symptoms (see Current Hypothesis by A. Abi-Dargham and related SRF news story for reviews). Dopamine in the striatum comes from two sources: the substantia nigra supplies the dorsal striatum via the nigrostriatal pathway, and the ventral tegmental area feeds the ventral striatum via the mesolimbic dopamine pathway.

Initial success with antipsychotic medications that act on the dopamine system have supported the hypothesis that dysregulated dopamine contributes to schizophrenia symptoms, and more recent imaging studies utilizing positron emission tomography (PET) have further validated this idea by enabling the visualization of striatal dopamine. Based on imaging studies, both dopamine synthesis and dopamine release seem to be magnified in the striatum in schizophrenia. The degree of dopamine increase appears to be related to psychotic symptom severity. Despite these findings, it is not clear that elevated dopamine is a cause or consequence of psychotic symptoms (for review, see Howes et al., 2007).

Prodromal schizophrenia is a phase that occurs prior to the onset of schizophrenia. Understanding the cause of symptoms could help to identify interventions directed at this early stage, which can precede the onset of hallucinations and delusions by several years (see related SRF news story). Prodromal symptoms can include anxiety, social isolation, as well as problems with concentration and attention.

The present study used 18Fdopa striatal PET imaging in 24 individuals meeting at-risk-mental-state (ARMs) criteria and compared dopaminergic activity in these subjects to activity in the brains of healthy volunteers and to people with schizophrenia. Prior research has shown that individuals who meet ARMs criteria have a risk of developing psychosis ranging from 15 percent to 54 percent after six months to one year (Haroun et al., 2006; Miller et al., 2002).

Dopamine activity was measured by using the imaging data to calculate what is known as a Ki value. Ki values represent the conversion of 18Fdopa by dopamine decarboxylase to F-fluoro-dopamine, similar to the conversion of L-dopa to dopamine, so the Ki value reflects the rate of dopamine synthesis and storage. When measurements were taken of the entire striatum, the mean Ki value was increased by 6.3 percent (effect size 0.75; (t34 = 2.2, P = .04) in the prodromal group and by 10.6 percent (effect size, 1.25; t17 = 2.5, P = 0.02) in the group with schizophrenia relative to the control group. When increases in a subdivision of the dorsal striatum known as associative striatum—important for integrating information from different regions of the cortex—were measured, even greater elevations were seen relative to controls: 7.3 percent in the prodromal group and 13.9 percent in the group with schizophrenia. Significant changes relative to controls were not seen in the sensorimotor region of the dorsal striatum or in the ventral (limbic) striatum. There were no statistically significant differences between the prodromal group and the group with schizophrenia for increases found in either the whole or the associative striatum.

Howes and coworkers also assessed the functional significance of these dopamine changes, examining whether a relationship exists between striatal dopamine levels and measures of psychopathology or neuropsychological performance. In the prodromal group, whole striatal Ki values positively correlated with several measures of schizophrenia symptom severity, including total comprehensive assessment of ARMs score (CAARMs; r = 0.48, P = 0.02) and positive and negative symptoms of schizophrenia score (PANSS) (r = 0.49, P = 0.01). The investigators also obtained positive correlations for the associative striatum using these measurements, although they found no relationship between measurements of depression or anxiety and any striatal dopamine activity, using the Hamilton Depression Rating Score or Hamilton Anxiety Rating Scale Score. Verbal fluency measures negatively correlated with striatal dopamine activity; these measurements were either significant or showed a trend for significance. Interestingly, in the group with schizophrenia there was no relationship between whole striatal Ki values and PANSS, CAARMs, or the Hamilton rating scores for depression and anxiety. Howes told SRF that “this may reflect a different stage of the illness: dopamine dysregulation may increase up to the onset of illness but not change further, although symptoms may fluctuate.”

According to the investigators, these data support the role of excessive subcortical dopamine as a precursor to schizophrenia, contributing potentially to both prodromal symptoms as well as changes in cognitive function, specifically verbal fluency. Interestingly, a recent report has linked the development of language dysfunction to the onset of hallucinations, suggesting that the two are related (Defreitas et al., 2008). The authors noted that decreases in dopamine activity in associative striatum were negatively correlated with verbal fluency, whereas changes in limbic striatal activity were not. Associative striatum may regulate verbal ability via connections with the prefrontal cortex (Haber, 2003; Middleton and Strick, 2000). This study supports the idea that associative striatal inputs may regulate verbal deficits, possibly through inputs to and from prefrontal cortical regions.

In their conclusions the authors noted that since all people with prodromal symptoms do not necessarily develop schizophrenia, increased striatal dopamine activity may confer a vulnerability to the onset of schizophrenia psychotic symptoms rather than indicate that a person will necessarily develop schizophrenia. In addition, Howes told SRF that, “Our finding that dopamine function is dysregulated in people at risk of developing schizophrenia provides a neurobiological rationale for the use of interventions that reduce the dopamine elevation in these people; by reducing the dopamine elevation such interventions may prevent the onset of schizophrenia in vulnerable individuals.”—Alisa Woods.

Reference:
Howes OD, Montgomery AJ, Asselin MC, Murray RM, Valli I, Tabraham P, Bramon-Bosch E, Valmaggia L, Johns L, Broome M, McGuire PK, Grasby PM. Elevated striatal dopamine function linked to prodromal signs of schizophrenia. Arch Gen Psychiatry. 2009 Jan;66(1):13-20. Abstract

Comments on News and Primary Papers
Comment by:  Anissa Abi-Dargham, SRF Advisor
Submitted 28 January 2009
Posted 28 January 2009

This paper introduces new knowledge and at the same time replicates many of the themes that have emerged in the area of dopamine research and schizophrenia. The new knowledge is that DA dysregulation precedes onset, and is present in the same anatomical area and with a similar magnitude to that observed in schizophrenia. It shows once again that the dopamine dysregulation in schizophrenia is one of the most replicated and consistent findings in the field.

The area of pathology within the striatum is, as described in schizophrenia, the associative, rather than the limbic or sensorimotor striatum (Kegeles et al., 2006). This represents the main area of projection of the DLPFC. Furthermore, this part of the striatum receives input from other limbic cortical areas (Haber et al., 2006) and may play a role in integrating emotions and cognition. Alterations in this integrative function could lead to misattributions or mislabelings leading to paranoia or “inappropriate” affect, in addition to the cognitive deficits.

The relationship to baseline psychotic symptoms, present for the prodrome but not detected in schizophrenia, as we have previously shown, too (Laruelle et al., 1999), is worth commenting on. It suggests that dopamine may play an essential role in the genesis of psychotic symptoms. This role may be most predominant early on in the disease, rather than later in the course of the illness. Later, symptoms may perpetuate for other reasons. Alternatively, it may be that their partial improvement due to treatment prior to the scan may make the relationship more difficult to detect, and that relationship would be detected if studies included only drug naïve patients. Either way, the relationship to severity of symptoms in the prodromal stage suggests that dopamine dysregulation may be an early part of the pathogenetic pathway, and not a subsequent consequence of other events. This is strengthened by the relationship to deficits on a verbal fluency task, suggesting again a general role for dopamine in the genesis of all symptom domains.

The next questions that emerge from these data are, How early in life is the DA alteration present and what are its effects on the developing brain and the relevant circuitry? As D2 overexpression in the striatum during development resulted in long-lasting alterations in cortical dopamine and cortical function in mice (Kellendonk et al., 2006), it may be that early alterations of D2 signaling within the associative striatum have effects on other targets within the associative striatum and along the whole integrated cortico-striato-thalamocortical circuit that become obvious only at onset. Identifying and halting this process early on are needed in order to prevent long-lasting deficits. In this regard, the paper does not present evidence that increased dopamine predicts conversion, which would be needed if one should propose a test of striatal dopamine for therapeutic intervention. For this to happen, large-scale imaging studies showing sensitivity and specificity of [18F]-DOPA as a biomarker for conversion are needed, similarly to studies conducted now in the field of Alzheimer disease using PET and tracers to label β amyloid.

References:

Kegeles L, Frankle W, Gil R, et al. Schizophrenia is associated with increased synaptic dopamine in associative rather than limbic regions of the striatum: implications for mechanisms of action of antipsychotic drugs. J Nucl Med. 2006(47):139P.

Haber SN, Kim KS, Mailly P, Calzavara R. Reward-related cortical inputs define a large striatal region in primates that interface with associative cortical connections, providing a substrate for incentive-based learning. J Neurosci. Aug 9 2006;26(32):8368-8376. Abstract

Laruelle M, Abi-Dargham A, Gil R, Kegeles L, Innis R. Increased dopamine transmission in schizophrenia: relationship to illness phases. Biol Psychiatry. 1999;46(1):56-72. Abstract

Kellendonk C, Simpson EH, Polan HJ, et al. Transient and selective overexpression of dopamine D2 receptors in the striatum causes persistent abnormalities in prefrontal cortex functioning. Neuron. Feb 16 2006;49(4):603-615. Abstract

View all comments by Anissa Abi-Dargham

Comments on Related News


Related News: Early Striatum Shrinkage—Canary Warning of Extra-pyramidal Symptoms?

Comment by:  Stephen Lawrie
Submitted 20 June 2010
Posted 22 June 2010

This is a striking finding, but it is difficult to know what motivated the study or how to interpret the results. The study is very small and was probably of an exploratory rather than hypothesis-testing nature, making replication doubly important. It is also unclear what sort of biological changes may underlie the apparent loss of volume in the putamen—as the authors say, it is unlikely to be cell damage or vascular. A reversible change over such a short period of time suggests possible changes in cellular fluid balance. Regardless, these results on exposure to IV drug in young healthy men may bear no relation to the effects of the drug in the routine and usually oral treatment of patients with schizophrenia and related conditions.

View all comments by Stephen Lawrie

Related News: Early Striatum Shrinkage—Canary Warning of Extra-pyramidal Symptoms?

Comment by:  Georg Winterer (Disclosure)
Submitted 10 January 2011
Posted 10 January 2011

I fully agree with the comment made by Stephen Lawrie on the paper of the Meyer-Lindenberg group (Tost et al., 2010) published in Nature Neursocience. In particular, I agree with his suggestion that cellular fluid balance may account for the haloperidol neuroplasticity finding in the striatum. This is because it is well known among psychiatrists with some pharmacology training that haloperidol has an effect on fluid balance. Canary stories (to borrow Victoria Wilcox's metaphor) with retrospective analysis of seven (!!) healthy subjects and without prior hypothesis that would have helped to account for potentially confounding variables (e.g., body fluid, electrolyte parameters, hormonal levels, etc.) in the study design should not be published. What we need in schizophrenia research are high-flying eagles—not canaries in golden cages (high-impact journals).

References:

Tost H, Braus DF, Hakimi S, Ruf M, Vollmert C, Hohn F, Meyer-Lindenberg A. Acute D2 receptor blockade induces rapid, reversible remodeling in human cortical-striatal circuits. Nat Neurosci. 2010 Aug; 13(8):920-2. Abstract

View all comments by Georg Winterer

Related News: Signs of Things to Come? Seeking Biomarkers for the Schizophrenia Prodrome

Comment by:  Thomas McGlashan
Submitted 21 January 2012
Posted 21 January 2012

Three very recent publications have detailed that biomarkers can identify and quantify high-risk or prodromally symptomatic subjects who subsequently undergo conversion to psychosis. McGuire and his group (Howes et al., 2011) used fluoro-dopa positron emission tomography scanning to measure dopamine synthesis. Koutsouleris et al. (Koutsouleris et al., 2011) used structural MRI data to develop a neuroanatomical classification system for predicting psychosis conversion, and Amminger et al. (Amminger et al., 2011) used capillary gas chromatography of erythrocyte membrane fatty acid levels to provide information about brain phospholipids. All measures were significantly successful in identifying high-risk or prodromally symptomatic subjects who went on to develop a first episode of psychosis.

These papers point to an exciting future in our efforts to elaborate easily identifiable risk factors that can pinpoint among clinically identified "prodromal" subjects those who are most likely to become psychotic. That such diverse measures proved to be successful in identifying "true positives" can be regarded as a milestone in this line of investigation. It represents a quantitative leap forward in our ability to reduce the uncertainty of predicting psychosis, and hints at the day when tragedies such as the one occurring in Tucson, Arizona, become a thing of the past.

References:

Howes OD, Bose SK, Turkheimer F, Valli I, Egerton A, Valmaggia LR, Murray RM, McGuire P. Dopamine Synthesis Capacity Before Onset of Psychosis: A Prospective [18F]-DOPA PET Imaging Study. Am J Psychiatry. 2011 Dec 1; 168: 1311-1317. Abstract

Koutsouleris N, Borgwardt S, Meisenzahl EM, Bottlender R, Möller HJ, Riecher-Rössler A. Disease Prediction in the At-Risk Mental State for Psychosis Using Neuroanatomical Biomarkers: Results From the FePsy Study. Schizophr Bull. 2011 Nov 10. Abstract

Amminger GP, Schäfer MR, Klier CM, Slavik JM, Holzer I, Holub M, Goldstone S, Whitford TJ, McGorry PD, Berk M. Decreased nervonic acid levels in erythrocyte membranes predict psychosis in help-seeking ultra-high-risk individuals. Mol Psychiatry. 2011 Dec 20. Abstract

View all comments by Thomas McGlashan