Stem cell signaling in newly diagnosed, antipsychotic-naive subjects with nonaffective psychosis

Widespread metabolic abnormalities have been described in newly diagnosed, antipsychotic-naive patients with nonaffective psychosis, including a shorter telomere,¹ abnormal glucose tolerance,² an increase in the pro-inflammatory molecule interleukin-6² and an increased pulse pressure.¹ Stromal-derived factor 1-alpha (SDF-1α), the major chemokine for adult stem cells (SCs), is involved in glucose regulation³ and is abnormal in diabetes.⁴ SDF1 is critical in homing, maintenance and mobilization of adult SCs.⁵ We tested the hypothesis that newly diagnosed, antipsychotic-naive patients with nonaffective psychosis would have a decreased concentration of circulating SDF-1α compared with control subjects.

The psychosis (N = 24) and control (N = 24) subjects were matched for race (Caucasian), gender, age, body mass index, smoking habit, cortisol blood levels, socioeconomic status and catchment area (Table 1). The two groups were matched before assaying SDF-1α concentrations. All subjects were interviewed using the Structured Clinical Interview for DSM-IV Axis I Disorders. Psychopathology was rated using the Positive and Negative Syndromes Scale (PANSS). Subjects in the psychosis group had a maximum lifetime antipsychotic exposure of 1 week and no antipsychotic use in the 30 days before the study, and had a diagnosis of nonaffective psychosis. Exclusion criteria for the control subjects included a history of psychosis or major depressive disorder. Additional general inclusion criteria were age from 18 to 64 years, no history of serious medical or neurological condition and not using any medication that impacts glucose tolerance. All subjects gave informed consent for participation in the study, which was conducted under the supervision of the local institutional review board.

Table 1.

Characteristics of nonaffective psychosis^a and control subjects

	Psychosis (N = 24)	Control (N = 24)	P-valueb
Mean age (s.d.) in years	30.4 (10.3)	26.8 (6.1)	0.144
Male/female	17/7	17/7	1.000
Mean body mass index (s.d.)c	22.6 (4.4)	23.9 (2.8)	0.247
Mean number of cigarettes per day (s.d.)	8.3 (9.0)	5.1 (7.4)	0.179
Mean cortisol blood levels in mg per 100 ml (s.d.)	18.7 (4.4)	21.2 (2.8)	0.095
Mean parental socioeconomic status (s.d.)d	34.7 (14.7)	42.4 (13.3)	0.086
Living in the catchment areae, n (%)	15 (62.5)	19 (70.8)	0.204

^aSixteen met criteria for schizophrenia, six for schizophreniform disorder and two for delusional disorder.

^bStatistical tests were t-tests except for gender and area of residence.

^cIn kg m⁻².

^dSocioeconomic status of the family of origin was assessed with the Hollingshead-Redlich scale.

^eCatchment area (Esquerra Eixample) in Barcelona. Esquerra Eixample is a relatively homogeneous middle class/upper middle class neighborhood in the center of the city.

Blood was drawn between 0800 and 0900 hours after an overnight fast. Plasma was collected on ice using EDTA and centrifuged for 15 min at 1000 × g within 30 min of collection. An additional centrifugation step of the separated plasma at 10 000 × g for 10 min at 2–8 °C was performed for complete platelet removal. Samples were aliquoted and stored at −80 °C. Quantitative determination of human CXCL12/SDF-1α was determined with Quantikine ELISA kit DSA00 (R&D Systems Inc., Minneapolis, MN, USA) according to the manufacturer’s instructions.

Mean (s.d.) SDF-1α blood levels were 1751 ng ml⁻¹(307) for the psychosis group and 1927 ng ml⁻¹ (281) for the comparison subjects (t = −2.076; P = 0.043; effect size r = 0.57; Figure 1). SDF-1α concentrations were significantly correlated with the PANSS conceptual disorganization item (r = 0.543; P = 0.006), but not with the severity of reality distortion (the sum of the delusions and hallucinatory behavior item scores (r = 0.34; P = 0.11)) or negative symptoms (the sum of the scores for the seven items of the negative syndrome subscale (r = 0.24; P = 0.25)).

Figure 1.

Mean blood concentrations of SDF-1α in newly diagnosed, antipsychotic-naive subjects with nonaffective psychosis (N = 24) and matched control subjects (N = 24). Error bars represent s.d. The group difference was significant (t = −2.076; P = 0.043).

This is the first report of SDF-1α blood levels in schizophrenia. Abnormalities in other chemokines have been described earlier in psychosis, including increased CCL11⁶ and CCL2.⁷ These chemokines and SDF-1α have similar functions, as all of them induce specific blood cells to leave the bloodstream and enter other tissues. Unlike these other chemokines, SDF-1α also plays a major role in promoting the release of SCs from the bone marrow and, after tissue damage, in recruiting circulating SCs that express CXCR4.^8,9 As CXCR4 is also expressed in lymphocytes, it could be argued that our results reflect increased lymphocyte trafficking rather than an effect related to SC. However, in our study, SDF-1α was reduced in the psychosis group compared with that in control subjects, whereas other studies reported increased chemokine levels.

Our results suggest that schizophrenia may have impairment in normal regeneration and repair. We hypothesize that expression of this chemokine, which attracts adult SC to damaged tissue, is downregulated, that is, decreased circulating concentrations of SDF-1α may mean less chemoattractant signal at sites of injury. Our results also raise the possibility that schizophrenia may be associated with a decrease in the number of circulating SC.

Along with other risk factors for diabetes and related conditions, such as poor health habits, poor access to care and medication side effects, abnormal function of adult SC may contribute to the high prevalence of medical problems found among patients. The correlation with disorganization raises the question of whether repair processes in the brain are also abnormal. However, without replication and further examination of SC function, these possibilities remain unproven.