Historical background of long-acting injectable antipsychotics Soon after the introduction of antipsychotics (APs) in the 1950s, poor adherence to oral formulations was found to be a critical issue. This led to the development in 1966 of the first long-acting injectable (LAI) AP fluphenazine enanthate, and fluphenazine decanoate some 18 months later, to reduce the incidence of side effects of the former [Johnson, 2009]. Haloperidol decanoate became available in Europe in 1981 and in the USA in 1986 [Knudsen, 1985]. Clinical trial results showed a dramatic reduction in the morbidity of schizophrenia [Gottfries and Green, 1974; Johnson, 2009]. However, the concept of LAIs for schizophrenia was not initially received warmly by the medical profession for fears of increased side effects, lack of efficacy, and the fact this was seen as an attempt by psychiatrists to impose a treatment upon patients without due regard to their feelings or rights [Johnson, 2009] as well as the potential for medicolegal problems [Glazer and Kane, 1992]. However, with subsequent surveys and trials suggesting their benefits [Rifkin et al. 1977; Schooler et al. 1980; Hogarty et al. 1979], LAIs became more widely adopted. The introduction of the oral second-generation APs (SGAs) brought claims of better tolerance and less severe side effects, even though their use may be hindered by metabolic syndrome [Meyer and Stahl, 2009]. They also have potential to prevent or reverse accelerated frontotemporal cortical grey matter decline, and to provide a greater degree of neuroprotection than first generation APs (FGAs) [Keefe et al. 2004; Robinson et al. 2006]. The introduction of SGAs led to a decline in the use of LAI FGAs [Patel et al. 2003; Patel and David, 2005]. However, it soon became clear that atypical characteristics did not bring better adherence rates with oral SGAs. The recent introduction of LAI SGAs allows psychiatrists once

The startle response is composed by a set of reflex behaviors intended to prepare the organism to face a potentially relevant stimulus. This response can be modulated by several factors as, for example, repeated presentations of the stimulus (startle habituation), or by previous presentation of a weak stimulus (Prepulse Inhibition [PPI]). Both phenomena appear disrupted in schizophrenia that is thought to reflect an alteration in dopaminergic and glutamatergic neurotransmission. In this paper we analyze whether the reported deficits are indicating a transient effect restricted to the acute phase of the disease, or if it reflects a more general biomarker or endophenotype of the disorder. To this end, we measured startle responses in the same set of thirteen schizophrenia patients with a cross-sectional design at two periods: 5 days after hospital admission and 3 months after discharge. The results showed that both startle habituation and PPI were impaired in the schizophrenia patients at the acute stage as compared to a control group composed by 13 healthy participants, and that PPI but not startle habituation remained disrupted when registered 3 months after the discharge. These data point to the consideration of PPI, but not startle habituation, as a schizophrenia biomarker.

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