Raimo K. R. Salokangas

Prediction of Psychosis in Adolescents and Young Adults at High Risk: Results From the Prospective European Prediction of Psychosis Study

CONTEXT Indicated prevention is currently regarded as the most promising strategy to attenuate, delay, or even avert psychosis. Existing criteria need improvement in terms of specificity and individual risk assessment to allow for better targeted and earlier interventions. OBJECTIVE To develop a differential predictive clinical model of transition to first-episode psychosis. DESIGN Prospective multicenter, naturalistic field study with a total follow-up time of 18 months. SETTING Six early-detection outpatient centers in Germany, Finland, the Netherlands, and England. PARTICIPANTS Two hundred forty-five help-seeking patients in a putatively prodromal state of psychosis according to either ultra-high-risk (UHR) criteria or the basic symptom-based criterion cognitive disturbances (COGDIS). MAIN OUTCOME MEASURE Incidence of transition to psychosis. RESULTS At 18-month follow-up, the incidence rate for transition to psychosis was 19%. Combining UHR and COGDIS yielded the best sensitivity. A prediction model was developed and included positive symptoms, bizarre thinking, sleep disturbances, a schizotypal disorder, level of functioning in the past year, and years of education. With a positive likelihood ratio of 19.9, an area under the curve of 80.8%, and a positive predictive value of 83.3%, diagnostic accuracy was excellent. A 4-level prognostic index further classifying the general risk of the whole sample predicted instantaneous incidence rates of up to 85% and allowed for an estimation of time to transition. CONCLUSIONS The prediction model identified an increased risk of psychosis with appropriate prognostic accuracy in our sample. A 2-step risk assessment is proposed, with UHR and cognitive disturbance criteria serving as first-step criteria for general risk and the prognostic index as a second-step tool for further risk classification of each patient. This strategy will allow clinicians to target preventive measures and will support efforts to unveil the biological and environmental mechanisms underlying progression to psychosis.

Presynaptic dopamine function in striatum of neuroleptic-naive schizophrenic patients

Presynaptic dopamine function (6-[18F]-fluorodopa uptake) in the brains of seven neuroleptic-naive first-admission schizophrenic patients and eight healthy controls was studied with positron emission tomography. The fluorodopa influx constant (Ki) in putamen was higher in the patients than in controls (average mean: 0.0149 vs 0.0129, p = 0.034). The changes in caudate were smaller but significantly lateralised to the left caudate. There was one catatonic schizophrenic patient in our sample. This patient had lower striatal Ki than any control. Alterations in striatal presynaptic dopamine function may constitute a part of disrupted neural circuits that predispose to schizophrenic psychosis.

Depressive symptoms and presynaptic dopamine function in neuroleptic-naive schizophrenia

We have previously reported aberrations in the striatal presynaptic dopamine function in neuroleptic-naive schizophrenic patients compared to healthy controls (Hietala, J., Syvälahti, E., Vuorio, K. et al., 1995. Lancet 346, 1130-1131). In this extended study we explore whether the altered presynaptic dopamine function correlates with the clinical symptomatology in schizophrenia. Striatal dopamine synthesis capacity (6-[18F]fluorodopa (FDOPA) uptake, Ki values) was studied with positron emission tomography in 10 neuroleptic-naive schizophrenic patients and 13 healthy controls. The clinical symptomatology was characterized with the Positive and Negative Symptom Scale (PANSS). The patients had an increased FDOPA uptake in striatum and lacked the asymmetry in caudate FDOPA uptake (p = 0.0005), confirming our earlier results. Left striatal FDOPA uptake (Ki) values correlated negatively with depressive symptoms in a highly significant manner. On the other hand, paranoid symptomatology correlated positively with right putamen FDOPA uptake at a trend level (rho = 0.73, p < 0.02). The lack of asymmetry in caudate Ki values did not associate with any dimension of psychopathology. The major finding in this study is that depressive symptoms in neuroleptic-naive first-admission schizophrenia are associated with low presynaptic dopamine function. This link appears to be hemisphere-related and may have drug-treatment implications, e.g., in prediction of response to D2 receptor blocking antipsychotic drugs. A possible connection between paranoid symptomatology and subcortical hyperdopaminergia is suggested, but this remains to be further verified.

Sex differences in striatal presynaptic dopamine synthesis capacity in healthy subjects

BACKGROUND There are sex differences in the clinical features of several neuropsychiatric illnesses associated with dopamine dysfunction. The effects of sex on brain dopaminergic function have been sparsely studied in human subjects using modern imaging techniques. We have previously reported that the apparent affinity of [(11)C]raclopride for striatal D(2) dopamine receptors in vivo is lower in women than in men, whereas D(2) receptor density is not different. This finding indirectly suggests that women have a higher synaptic concentration of dopamine in the striatum. We explored further the basis of this phenomenon in an independent study and hypothesized that striatal presynaptic dopamine synthesis capacity would also be elevated in women. METHODS A total of 23 healthy men and 12 healthy women (age range 20-60 years) were studied using positron emission tomography and [(18)F]fluorodopa. RESULTS Women had significantly higher striatal [(18)F]fluorodopa uptake (Ki values) than men. The difference was more marked in the caudate (+26%) than in the putamen (+12%). In addition, there was a negative correlation between striatal [(18)F]fluorodopa Ki values and age in men but not in women. CONCLUSIONS The results further substantiate sex differences in striatal dopaminergic function in humans. This finding may be associated with sex differences in vulnerability and clinical course of neuropsychiatric disorders with dopaminergic dysregulation, e.g., schizophrenia, alcohol dependence, and Parkinsons disease.

Gender differences in depressive symptoms: An artefact caused by measurement instruments?

BACKGROUND According to studies depression and depressive symptoms are more prevalent in females than in males. It is possible, however, that instruments meant to measure depressiveness are gender-biased. METHOD This was studied by comparing two screening instruments (the Beck Depression Inventory (BDI) and the Depression Scale (DEPS) within the same population. The study sample consisted of 330 subjects taken from general population in south-western part of Finland. RESULTS The mean BDI scores were borderline higher in females than in males, with no gender difference in DEPS scores. The difference between BDI and DEPS scores was significant between genders but not for other variables. Crying and lost interest in sex were the items on which females scored higher. CONCLUSIONS It has been argued that these items, crying and lost interest in sex, are biologically, psychologically and culturally related to female gender and, therefore, give gender-biased results in measuring depressiveness. CLINICAL IMPLICATIONS It is important to realise that some instruments meant for screening depression may include gender-biased items and therefore give too high scores of depressiveness in females. LIMITATIONS The study is based on self-filled scales and its results cannot, therefore, be directly generalised to clinical depression.

Striatal Dopamine Synthesis in First-degree Relatives of Patients with Schizophrenia

BACKGROUND First degree relatives (FDR) of patients with schizophrenia have higher risk of developing schizophrenia than the general population. Previous positron emission tomography (PET) studies have shown that striatal presynaptic dopamine synthesis capacity is increased in schizophrenia. We investigated whether this same phenomenon is shared by individuals with increased genetic risk for schizophrenia. METHODS We used 6-[18F]-fluorodopa (FDOPA) PET imaging to measure striatal dopamine synthesis capacity. We studied 17 nonpsychotic subjects with an FDR with schizophrenia. This group was compared to 17 healthy subjects with no FDRs with schizophrenia. RESULTS A conventional region of interest (ROI)-analysis indicated that FDOPA uptake (K(i)) in the caudate-putamen was statistically significantly higher in the FDR group than in the control group. A voxel-level analysis confirmed these results. CONCLUSIONS These results suggest that the changes of striatal presynaptic dopamine synthesis seen previously in neuroleptic-naive schizophrenic patients is also present in FDRs of patients with schizophrenia. These findings have implications for the early detection of psychosis as well as for pharmacological interventions in individuals at risk for psychosis.

Disability in people clinically at high risk of psychosis

BACKGROUND Decline in social functioning occurs in individuals who later develop psychosis. AIMS To investigate whether baseline differences in disability are present in those who do and those who do not make a transition to psychosis in a group clinically at high risk and whether disability is a risk factor for transition. METHOD Prospective multicentre, naturalistic field study with an 18-month follow-up period on 245 help-seeking individuals clinically at high risk. Disability was assessed with the Disability Assessment Schedule of the World Health Organization (WHODAS-II). RESULTS At baseline, the transition group displayed significantly greater difficulties in making new friends (z = -3.40, P = 0.001), maintaining a friendship (z =-3.00, P = 0.003), dealing with people they do not know (z =-2.28, P = 0.023) and joining community activities (z =-2.0, P = 0.05) compared with the non-transition group. In Cox regression, difficulties in getting along with people significantly contributed to the prediction of transition to psychosis in our sample (β = 0.569, s.e. = 0.184, Wald = 9.548, P = 0.002, hazard ratio (HR) = 1.767, 95% CI 1.238-2.550). CONCLUSIONS Certain domains of social disability might contribute to the prediction of psychosis in a sample clinically at high risk.

Axis-I disorders and vulnerability to psychosis

BACKGROUND The psychopathology that manifests during the prodromal phase of first-episode psychosis is varied. Little is known about the clinical diagnoses of subjects with so-called prodromal or psychotic-like symptoms. METHOD Samples of psychotic patients, first-degree relatives (FDRs) of psychotic, or severely ill patients, treatment-seeking patients, and a random community sample (in all 157 subjects) were assessed by the Structured Interview for Prodromal Symptoms (SIPS) and the SCID-I. Vulnerability to psychosis (VTP) was defined by severity of positive symptoms reported in the SIPS interview and associated with lifetime SCID-I diagnoses. RESULTS The number of lifetime diagnoses received increased linearly as the SIPS symptoms approached more psychotic-like phenomena. All VTP subjects received on average 2.5, and currently prodromal subjects 2.9 lifetime SCID-I diagnoses, while the corresponding figure for non-VTP subjects was 0.7 (p<0.0001). Mood disorders and comorbid anxiety disorders were particularly common. CONCLUSION Vulnerability to psychosis seems to be associated with a high number of lifetime Axis-I diagnoses. Occurrence of anxiety disorders is remarkable, and most VTP subjects can be diagnosed with a lifetime mood disorder. VTP subjects require careful assessment of mood and anxiety symptoms and adequate treatment for their multiple disorders.

Axis I diagnoses and transition to psychosis in clinical high-risk patients EPOS project: prospective follow-up of 245 clinical high-risk outpatients in four countries.

BACKGROUND In selected samples, a considerable number of patients at clinical high risk of psychosis (CHR) are found to meet criteria for co-morbid clinical psychiatric disorders. It is not known how clinical diagnoses correspond to or even predict transitions to psychosis (TTP). Our aim was to examine distributions of life-time and current Axis I diagnoses, and their association with TTP in CHR patients. METHODS In the EPOS (European Prediction of Psychosis Study) project, six European outpatient centres in four countries examined 245 young help-seeking patients, who fulfilled the inclusion criteria for clinical risk of psychosis according to the Structured Interview for Prodromal Syndromes (SIPS 3.0) or the Bonn Scale for the Assessment of Basic Symptoms - Prediction List basic symptoms (BASBS-P). Patients who had experienced a psychotic episode lasting more than one week were excluded. Baseline and life-time diagnoses were assessed by the Structured Clinical Interview for DSM-IV (SCID-I). TTP was defined by continuation of BLIPS for more than seven days and predicted in Cox-regression analysis. RESULTS Altogether, 71% of the CHR patients had one or more life-time and 62% one or more current SCID-I diagnosis; about a half in each category received a diagnosis of life-time depressive and anxiety disorder. Currently, 34% suffered from depressive and 39% from anxiety disorder. Four percent received a current SCID diagnosis of bipolar, and 6.5% of somatoform disorder. During follow-up, 37 (15.1%) patients had developed full-blown psychosis. In bivariate analyses, current non-psychotic bipolar disorder associated significantly with TTP. In multivariate analyses, current bipolar disorder, somatoform and unipolar depressive disorders associated positively, and anxiety disorders negatively, with TTP. CONCLUSIONS Both life-time and current mood and anxiety disorders are highly prevalent among clinical help-seeking CHR patients and need to be carefully evaluated. Among CHR patients, occurrence of bipolar, somatoform and depressive disorders seems to predict TTP, while occurrence of anxiety disorder may predict non-transition to psychosis.

Whither the Attenuated Psychosis Syndrome

After 4 years of debate, a decision has been made. The attenuated psychosis syndrome (APS) will not be a coded diagnosis in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). Formerly known as the psychosis risk syndrome, the proposed diagnosis was based on criteria developed in the mid-1990s that were informed by a comprehensive review of retrospective studies on the prodromal phase of nonaffective psychosis.1 These criteria aimed to identify prospectively people in the prodrome of schizophrenia and other psychotic disorders and have been variously titled “ultra high risk (UHR),” “clinical high risk (CHR),” “at risk mental state (ARMS),” and the “prodromal stage,” and included a group with attenuated (subthreshold) positive psychotic symptoms.2 The criteria are associated with rates of onset of psychotic disorder substantially higher than in the general population3 and other clinical populations.4 A recent meta-analysis reported the rate of onset of a psychotic disorder to be 36% after 3 years.5 About 73% of those developing a psychotic disorder fulfill criteria for schizophrenia spectrum psychoses.6 It should be noted that these data are from treated samples consisting of patients referred to specialist clinical services.