Medical Hypotheses 85 (2015) 367–370

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Early antipsychotic intervention and schizophrenia Yu-Yin Yang a, Chao-Lin Lu b, Shih-Mao Lo b, Chia-Ho Peng b, Yia-Ping Liu c,d,⇑ a

Nutrition Unit, Beitou Branch, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC Department of Psychiatry, Beitou Branch, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC c Department of Physiology and Biophysics, National Defense Medical Center, Taipei, Taiwan d Department of Psychiatry, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC b

a r t i c l e

i n f o

Article history: Received 20 January 2015 Accepted 18 May 2015

a b s t r a c t Schizophrenia is a major mental disorder in which patients’ cognitive functions gradually deteriorate. Pharmacological intervention with antipsychotics has proven effective, yet it is still debatable whether to initiate treatment in patients’ premorbid stage. Based on the developmental origins of schizophrenia, we hypothesize that for those who are at high risk for schizophrenia, particularly with gating problems, an early pharmacological intervention would be beneficial. We performed a pilot rodent study to evaluate this hypothesis. Our results demonstrated that isolation rearing-induced sensorimotor gating dysfunction could be reversed by a chronic risperidone regimen initiated at different age time points. As expected, interventions that we initiated earlier (in adolescent stage) appeared to have better efficacy than interventions initiated four weeks later (in young adult stage). Our hypothesis may contribute new insight for both prevention and treatment of schizophrenia. Ó 2015 Elsevier Ltd. All rights reserved.

Introduction Schizophrenia is a major mental disorder in which patients suffer from multidimensional malfunctions in a deteriorating manner [1]. Pharmacological intervention with antipsychotics has been proven effective in managing the symptoms of schizophrenic patients, thus resulting in a better prognosis [2]. However, whether an earlier intervention is necessary remains unknown. Not taking antipsychotics in the prodromal phase of schizophrenia mainly comes from the fact that (i) symptoms are not full-blown in the prodromal stage and some adolescents with prodromal signs did not show any sign of psychiatric illness later (i.e., false-positive) [3,4], (ii) there is a potential risk of stigmatizing patients as psychotic and doomed to chronic illness [5,6], and (iii) drugs may cause long-term side effects with possible morphological changes in the brain [7,8]. This evidence results in an ethical dilemma regarding early antipsychotic intervention [9]. Thus, early antipsychotic intervention is a topic involving ethics, neuroscience, preventive medicine, and health policy. However, the introduction of second-generation antipsychotics (SGAs) that were developed in the mid-1990s led to a paradigm

⇑ Corresponding author at: Department of Physiology and Biophysics, Department of Psychiatry, National Defense Medical Center, 161 Minchuan East Rd., Sec. 6, Taipei 114, Taiwan, ROC. Tel.: +886 2 87923100x18614. E-mail address: [email protected] (Y.-P. Liu). 0306-9877/Ó 2015 Elsevier Ltd. All rights reserved.

shift in early intervention ethics; SGAs were proven to have equal efficacy in comparison with traditional neuroleptics with fewer side-effects [5], and SGAs were used to prevent the relapse of the symptoms [9]. The rationale is based on considering schizophrenia to be a developmental disorder. Thus, the biological method should help impede the progress of the disorder and prevent the patients from receiving too much biochemical disturbance before they are aware of the symptoms. Developmental theory suggests that the evolution of schizophrenia follows a dynamic process. This process starts early in patients’ lives, and as time goes by, symptoms become full-blown around patients’ puberty stages. Their performance, including cognitive functions in particular, is gradually disabled in an irreversible manner thereafter [10]. Developmental theory maintains that the growth of an individual comprises several stages in a scheduled order, in which each stage must be satisfactorily resolved [11]. Based on this conceptual framework, perceptual symptoms such as auditory and visual hallucinations, among other cardinal characteristics of schizophrenia, may be related to certain developmental deviations with a pathological origin. This is particularly relevant in terms of sensory gating dysfunction, as it fails to filter out unimportant or unnecessary stimuli from the environment [12]. This failure is hypothetically considered to be relevant to the pathogenesis of hallucination [13]. However, neurodevelopmental evidence also reveals that negative symptoms in patients’ premorbid stages or first psychotic episodes respond poorly to antipsychotics [14]. Pre-attentional gating dysfunction


Y.-Y. Yang et al. / Medical Hypotheses 85 (2015) 367–370

would be potentially useful in defining the appropriate target population for early antipsychotic intervention.

Evaluation of the hypothesis

recognizing novel objects [15,16], attentional set-shifting [17,18], and gating pre-attentional sensorimotor stimulus ability [19]. IR rats are hyperactive in their central dopaminergic system, which is the common mechanism shared by sensorimotor gating deficit and schizophrenia [20]. However, the interpretation of schizophrenia based on IR effects should be noted because some of these effects are strain and sex-dependent [21,22]. IR rats are particularly suitable to be employed in the developmental theory of schizophrenia because these rats have been socially isolated from their early life. Increasing evidence has demonstrated that this sensorimotor gating deficit is unable to be reversed by re-socialization; therefore, a time window or so-called critical period for the normal gating ability to develop exists [23,24]. Accordingly, if our hypothesis is correct, earlier pharmacological intervention should be more beneficial in recovering IR-induced sensorimotor gating impairment.

Establishment of rodent model of schizophrenia with gating dysfunction characteristics

Methods and study design

We employed a schizophrenia rodent model to evaluate our hypothesis. The model is based on developmental theory and is known to cause a gating problem. Rats reared in social isolation from weaning (isolation rearing, IR) are acknowledged to model schizophrenia-spectrum disorders; they show impairments in

Twenty-eight IR rats (weaned at postnatal day 21) in adolescence (postnatal seven weeks) or young adulthood stages (postnatal 11 weeks) were randomly assigned to a saline or risperidone regimen (1 mg/kg/day, for four weeks, for each group, N = 4, see Fig. 1). Eight social control rats were employed to contrast the

Hypothesis The hypothesis described here is an extension of what is mentioned above, with a potentially pragmatic rationale in terms of how to reverse or alleviate the gating dysfunction-related endophenotype of schizophrenia. We hypothesize that early antipsychotic intervention, particularly before the emergence of full-blown schizophrenic symptoms (i.e., at premorbid stage), would be particularly beneficial in patients with sensory gating problems.

Fig. 1. There is no significant effect on startle reactivity (arbitrary units) between isolation rearing (IR) and social control (SOC) rats (A) or between saline or risperidone adolescent (B) or young adult (C) IR rats. Isolation reared (IR) rats have an inferior prepulse inhibition ability in comparison with their social controls (SOC) (D). Early intervention is beneficial in IR-induced sensorimotor gating deficit (adolescent IR/Risperidone, adolescent IR/Saline, young adult IR/Risperidone, and young adult IR/Saline, for each group, N = 4) because risperidone is more effective in adolescent (E) rats in comparison with young adult IR rats (F), and the risperidone-increased PPI in adolescent IR rats is higher than that of young adult IR rats. Data are represented as group averages ± SEM. *P < 0.05, ⁄⁄P < 0.01.

Y.-Y. Yang et al. / Medical Hypotheses 85 (2015) 367–370

IR-induced PPI deficit. Risperidone is a second-generation antipsychotic (SGAs) that exerts its effects via antagonism to both dopaminergic and serotoninergic receptors and is confirmed to reverse IR-induced sensorimotor gating dysfunction in rats [25,26]. We compared the drug effects in different aged IR rats (adolescent vs. young adult) on sensorimotor gating by measuring the ability to attenuate the startle response (equal to the eye-blink reflex in humans) [27] when the startle-eliciting stimulus is preceded by a weak prepulse; this ability is referred to as prepulse inhibition (PPI). The PPI testing paradigm was described previously by Liu and colleagues [22,23]. The acoustic startle response and PPI tests were performed in startle chambers (SR-LAB; San Diego Instrument, San Diego, CA). Startle responses were induced by the speaker mounted 24 cm above the animal to provide background noise (65 dB), startle stimuli (120 dB), and prepulse stimuli (77 dB) and the PPI was calculated according to the formula:

½1  ðstartle response for prepulse þ pulse pairÞ=


Conflict of interest statement None. Acknowledgments The study was supported by the Tri-Service General Hospital Beitou Branch (BAFH-101-01 and BAFH-102-03) and National Defense Medical Center (grant number MAB102-83). The authors thank anonymous reviewers for very helpful comments on a draft of the paper. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at 014.

ðstartle response for startle stimuli aloneÞ  100%: References Effects of chronic antipsychotic regimen initiated at different age on IR-induced sensorimotor gating impairment Our results showed that (i) startle reactivity increased with age [28] but was not affected by rearing condition (A–C, Fig. 1), (ii) IR rats had an inferior PPI in comparison with their social controls, and (iii) the chronic risperidone regimen effectively reversed the IR-induced PPI deficit (D–F, Fig. 1). As expected, the earlier intervention appeared to have better efficacy than the intervention initiated four weeks later. The early intervention used in the present study started at seven weeks after birth, corresponding to the adolescent stage in rats. For schizophrenia in humans, pharmacological intervention at that age is highly controversial because it is still during the premorbid stage of the disorder and patients are relatively asymptomatic [29] or only present with negative symptoms [14] at that time. In fact, early antipsychotic intervention is a difficult decision for psychiatrists for both ethical and scientific reasons [30]. Pharmacological intervention, if necessary, should be only considered in individuals who are at high risk to develop schizophrenia [31]. Our data that IR-induced PPI deficit can be benefited more if the antipsychotic intervention is initiated earlier seems to support this necessity. This result should be interpreted with caution and limitation because the rodent PPI deficit is at best similar to an endophenotype of schizophrenia, rather than a diagnostic symptom of this disorder. It refers only to candidates with problems processing pre-attentional information, for example, indexed by an abnormal eye-blink reflex in humans [27]. It is important to note that for patients’ first episodes of psychosis non-pharmacological interventions such as cognitive behavioral therapy and supportive counseling have revealed significant advantages in functioning outcome [32] and adaptation to illness [33]. Earlier antipsychotic intervention is worth considering for inclusion in the treatment protocol together with non-pharmacological interventions for individuals at a high risk of suffering from schizophrenia of a developmental nature.

Conclusion In summary, our data support the neurodevelopmental hypothesis of schizophrenia, and a developmentally critical period for this disorder exists. Early pharmacological intervention may provide a therapeutic benefit, particularly targeting patients who have problems processing pre-attentional information.

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Early antipsychotic intervention and schizophrenia.

Schizophrenia is a major mental disorder in which patients' cognitive functions gradually deteriorate. Pharmacological intervention with antipsychotic...
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