The elegant studies of Oliver Howes and colleagues (Howes et al., 2011; Howes et al., 2009; Howes et al., 2011) have contributed valuable information regarding the high-risk state and dopamine (DA). Because of these studies, it is now clear that striatal dopamine dysregulation precedes onset of psychosis, relates to symptoms, and affects the associative striatum most predominantly, at least initially, extending into the sensorimotor subregion with time (Howes et al., 2011), while the ventral striatum remains relatively spared. These are difficult studies in terms of recruitment, characterization, and retention of subjects for longitudinal follow-up, and represent a great contribution to our field.
The paper discussed here (Howes et al., 2011) expands the initial cohort of 24 subjects at ultra high (Howes et al., 2009) risk by adding six patients to the group. The authors also removed the schizotypal patients (n = 6) from the overall sample on the premise that these patients have elevated dopamine synthesis rates but do not progress to psychosis at the same rate as the remaining subjects do. This highlights the complexity of the clinical assessments in this population. One may argue that if schizotypal patients were included in the initial cohort, they must have displayed signs of “attenuated symptoms” as described, so they fit in the categorization of ultra high-risk group, and there should be little reason to consider them separately at this point. If considered separately and removed from the initial cohort, would that affect the results of the initial study? The authors may want to provide a revised analysis and a revised effect size for the initial sample published in 2009.
The relationship to baseline symptoms is striking, and has not been routinely observed in studies of patients with schizophrenia (Abi-Dargham et al., 1998; Laruelle et al., 1996). The lack of relationship between striatal DA and psychotic symptoms at baseline in schizophrenia, unlike the high-risk state, may be due to the added noise related to effects of duration of illness and treatment on symptoms, which may diminish the strength of this relationship in more chronic and previously treated patients. It also underscores very clearly that dopamine is essential to the emergence of symptoms in a vulnerable brain at the time of “high risk,” and to their mobilization with psychostimulants or stress, but DA may not be as clearly related to symptoms in the chronic phase.
The fact that increased dopamine synthesis affects the associative, and on longitudinal assessment, the sensorimotor striatal subregions is also an interesting observation, not only because of the regions affected, but also because of the regions unaffected. It is surprising that the ventral striatum (VST) does not exhibit the excess dopamine that was historically postulated to be present in limbic dopaminergic pathways and to be associated with psychosis. It has become clear from these findings and from our studies in patients with schizophrenia (Kegeles et al., 2010) that psychotic symptoms are related to excessive dopamine in the head of the caudate, an area of integration between orbitofrontal “limbic” cortex and dorsolateral prefrontal “cognitive” cortex (Haber et al., 2006), and this integration may be at the core of misattributions of meaning or significance that underlie the psychotic thinking. The absence of increase in dopamine in the limbic striatum may be related to the low motivation and anhedonia that is a core feature of the negative symptoms of the illness. In the group, there was no overall abnormality of dopamine synthesis in VST; however, there could be a variable range that may relate to the presence and severity of anhedonia. More specific assessments of functions related to the ventral striatum may be necessary to understand the role of dopamine in the ventral striatum in the pathophysiology of schizophrenia.
Will serial scanning be helpful to identify patients needing treatment? Will it increase our ability to detect patients early on and prevent progression? Identifying high risk before DA dysregulation may be the best therapeutic window for non-dopaminergic drugs that are currently under development. However, the screening itself relies on detecting increased dopamine function, which may already be too late for non-dopaminergic interventions to be effective. In other terms, although very valuable, detecting high-risk subjects by targeting their DA phenotype may be already too late to intervene most optimally. Searching for predecessors to the DA dysregulation may be the best way to optimize prevention.
Howes O, Bose S, Turkheimer F, Valli I, Egerton A, Stahl D, et al. Progressive increase in striatal dopamine synthesis capacity as patients develop psychosis: a PET study. Mol Psychiatry. 2011;16(9):885-6. Abstract
Howes OD, Montgomery AJ, Asselin MC, Murray RM, Valli I, Tabraham P, et al. Elevated striatal dopamine function linked to prodromal signs of schizophrenia. Arch Gen Psychiatry. 2009;66(1):13-20. Abstract
Howes OD, Bose SK, Turkheimer F, Valli I, Egerton A, Valmaggia LR, et al. Dopamine Synthesis Capacity Before Onset of Psychosis: A Prospective [18F]-DOPA PET Imaging Study. Am J Psychiatry. 2011. Abstract
Abi-Dargham A, Gil R, Krystal J, Baldwin R, Seibyl J, Bowers M, et al. Increased striatal dopamine transmission in schizophrenia: confirmation in a second cohort. Am J Psychiatry. 1998;155:761-7. Abstract
Laruelle M, Abi-Dargham A, van Dyck CH, Gil R, De Souza CD, Erdos J, et al. Single photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug free schizophrenic subjects. Proc Natl Acad Sci USA. 1996;93:9235-40. Abstract
Kegeles L, Abi-Dargham A, Frankle W, Gil R, Cooper T, Slifstein M, et al. Increased synaptic dopamine in associative regions of the striatum in schizophrenia. Archives of General Psychiatry. 2010;67((3)):231-9. Abstract
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. 2006;26(32):8368-76. AbstractView all comments by Anissa Abi-Dargham
Howes et al. make an important contribution in reporting increased striatal dopamine synthesis in a patient/subject cohort at ultra high risk for psychosis. Most interesting is the correlation between dopamine synthesis and transition to psychosis. An important milestone in the dopamine hypothesis of schizophrenia came with in-vivo neuroimaging evidence of increased dopamine release in persons with schizophrenia reported by Breier and colleagues (Breier et al., 1997) and by Laruelle and colleagues (Laruelle et al., 1996). This was the first direct evidence for the dopamine hypothesis. Howes et a. cite recent reviews by Abi-Dargham and others, and a meta-analysis is now available with advance access in the Schizophrenia Bulletin (Fusar-Poli and Meyer-Lindenberg, 2011) for the interested reader.
This report is timely for several reasons:
Attenuated psychosis syndrome (APS) may be recommended as a disorder in
DSM-5 (see American Psychiatric Association DSM-5 Development). The debate is intense (and has included an SRF online discussion). I have participated in the debate as chair of the psychosis work group for DSM-5 and find the discussion most informed when the following facts are kept in mind:
For more on this issue, Jim van Os and I have discussed the two sides of the DSM-5 debate elsewhere (Carpenter and van Os, 2011).References:
Breier A, Su TP, Saunders R, Carson RE, Kolachana BS, de Bartolomeis A, Weinberger DR, Weisenfeld N, Malhotra AK, Eckelman WC, Pickar D. Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: evidence from a novel positron emission tomography method. Proc Natl Acad Sci USA. 1997 Mar 18;94(6):2569-74. Abstract
Laruelle M, Abi-Dargham A, van Dyck CH, Gil R, D'Souza CD, Erdos J, McCance E, Rosenblatt W, Fingado C, Zoghbi SS, Baldwin RM, Seibyl JP, Krystal JH, Charney DS, Innis RB. Single photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug-free schizophrenic subjects. Proc Natl Acad Sci U S A. 1996 Aug 20;93(17):9235-40. Abstract
Fusar-Poli P and Meyer-Lindenberg A. STRIATAL PRESYNAPTIC DOPAMINE IN SCHIZOPHRENIA, PART II: META-ANALYSIS OF [18F/11C] DOPA PET STUDIES.
Dazzan P, Soulsby B, Mechelle A, Wood SJ, Velakoulis D, Phillips LJ, Yung AR, Chitnis X, Lin A, Murray RM, McGorry PD, McGuire PK, Pantelis C. Volumetric Abnormalities Predating the Onset of Schizophrenia and Affective Psychoses: An MRI Study in Subjects at Ultrahigh Risk of Psychosis Schizophr Bull sbr035 first published online April 25, 2011 doi:10.1093. Abstract
Fusar-Poli P. Voxel-wise meta-analysis of fMRI studies in patients at clinical high risk for psychosis. J Psychiatry Neurosci. 2011 Nov 1, 36(6):110021. Abstract
Ziermans TB, Sschothorst PF, Sprong M, Magnee MJ, van Engeland H, Kemner C. Reduced prepulse inhibition as an early vulnerability marker of the psychosis prodrome in adolescence. Schizophr Res. 2012. Jan, 134(1):10-5. Abstract
Cornblatt BA, Carrion RE, Addington J, Seidman L, Walker EF, Cannon TD, Cadenhead KS, McGlashan TH, Perkins DO, Tsuang MT, Woods SW, Heinssen R, Lencz T. Risk factors for psychosis: Impaired social and role functioning. Schizophr Bull. 2011. Nov 10, doi:10.1093. Abstract
Tandon N, Montrose D, Shah J, Rajarethinam RP, Diwadkar VA, Keshavan MS. Early prodromal symptoms can predict future psychosis in familial high-risk youth. J Psychiatr Res, 2012, 46(1):105-110. Abstract
Werbeloff N, Drukker M, Dohrenwend BP, Levav I, Yoffe R, van Os J, Davidson M, Weiser M. Self-reported attenuated psychotic symptoms as forerunners of severe mental disorders later in life. Arch Gen Psychiatry, 2012, Jan 2. Abstract
Fusar-Poli P, Radua J, McGuire P, Borgwardt S. Neuroanatomical Maps of Psychosis Onset: Voxel-wise Meta-Analysis of Antipsychotic-Naive VBM Studies Schizophr Bull sbr134 first published online November 10, 2011 doi:10.1093. Abstract
American Psychiatric Association DSM-5 Development
Carpenter WT and van Os J. Should attenuated psychosis be a DSM-5 diagnosis? Am J Psychiatry. 2011 May;168(5):460-3. AbstractView all comments by William Carpenter
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.
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. AbstractView all comments by Thomas McGlashan