Can age at sexual maturity act as a predictive biomarker for prodromal negative symptoms?

Abstract

Background

Puberty and reproductive hormones have been identified as having a potential role in schizophrenia. Earlier reports have suggested associations between later age at puberty and schizophrenia in males. Similarly, associations have been reported between testosterone levels and psychotic symptoms. In this report, we examined the association between age at puberty and prodromal symptoms of psychosis.

Methods

58 child or adolescent family members of individuals with schizophrenia were interviewed using the Scale of Prodromal Symptoms and the Tanner Maturational Scale. Age at Tanner pubertal stage was determined and regression analyses were used to explore associations between prodromal symptoms and age at puberty.

Results

Among males, delayed age at puberty was associated with greater severity of prodromal symptoms; the association between negative prodromal symptoms and delayed age was significant (p = 0.001). In females, the association was not statistically significant.

Conclusions

Our results suggest that delayed age at puberty may be associated with negative prodromal symptoms of schizophrenia in males. Our findings suggest that delayed age at puberty could potentially be a predictive biomarker for psychopathology in males at risk for schizophrenia.

Introduction

The search for early markers of psychosis has been a long and elusive process. A number of putative clinical and biological markers have been implicated including neurological soft signs (Heinrichs and Buchanan, 1988, Smith et al., 1999, Chan et al., 2010), abnormal eye movements (Campion et al., 1992, Lee and Williams, 2000), cortical gyrification patterns (Palaniyappan and Liddle, 2012) and more recently mismatch negativity (Nagai et al., 2013). However, there is still a need to identify methods of predicting psychosis. One suggested clinical biomarker relates to the role of reproductive hormones and age at puberty. Saugstad (1989) commented on the potential link between age at puberty and psychotic illnesses. She stated that early maturing females are more prone to developing affective psychosis while late maturing males are more prone to developing schizophrenia. Further, she hypothesized that these differences could be secondary to an altered rate of elimination of synapses in early maturing females and reduced synaptic density in the late maturing males. Cohen et al. (1999) noted that earlier age at puberty was associated with later age of onset of schizophrenia in women; in men, however, this association was in the opposite direction. Gruzelier and Kaiser (1996) noted that both males and females with extreme variations in age at onset of puberty scored higher on various schizotypy measures, including unreality, social withdrawal and anhedonia.

Puberty is associated with a pulsatile release in gonadotrophin releasing hormone (GnRH), leutinizing hormone (LH), androgens and estrogen (Veldhuis, 1996); both androgens and estrogen have been identified as being neuroprotective (Bialek et al., 2004, Markham, 2012). Thus, delayed puberty and delayed exposure of brain matter to the reproductive hormones can adversely affect critical brain processes during puberty. The role of neurosteroids, including testosterone, DHEA and estrogen in schizophrenia has been examined in depth. Estrogen has been identified as a potential explanation for the delayed onset of psychosis in women and the premenstrual exacerbations of psychotic symptoms (Kendell et al., 1987, Mahe and Dumaine, 2001, Bergemann et al., 2002). The association between testosterone levels and chronic schizophrenia (Markham, 2012) in males has, however, been controversial with some authors reporting a positive association between low testosterone and chronic schizophrenia and others being unable to confirm the association. Besides chronic schizophrenia, studies have examined testosterone levels in individuals at high risk (HR) of developing psychosis (Van Rijn et al., 2011) and first episode psychosis (FEP) (Huber et al., 2005, Ceskova et al., 2007) with varied results. Van Rijn et al. (2011) and Huber et al. (2005) noted lower testosterone levels in their groups of HR and FEP participants, while Ceskova et al. (2007) were unable to confirm the association. However, most authors agree that these differences appear to be driven by negative symptoms (Markham, 2012). In an earlier paper, Keshavan and Hogarty (1999) proposed that delayed exposure to testosterone may affect the naturally tuned pruning of glutamatergic pyramidal neurons in the cortex and association areas. Studies of young relatives at high risk for psychosis can potentially shed light on this important issue.

In this study, we aimed to examine the following hypotheses: 1. Delayed age at onset of puberty will be associated with greater prodromal symptoms of psychosis in males. 2: An earlier age of onset of puberty will be associated with greater prodromal symptoms in females. We examined these hypotheses in a group of child or adolescent relatives assessed as part of a longitudinal study of familial high risk subjects.