Antipsychotic Interventions in Prodromal Psychosis ...

Antipsychotic Interventions in Prodromal Psychosis

Chen-Chung Liu & Arsime Demjaha

CNS Drugs ISSN 1172-7047 CNS Drugs DOI 10.1007/s40263-013-0046-1

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Author's personal copy CNS Drugs DOI 10.1007/s40263-013-0046-1

REVIEW ARTICLE

Antipsychotic Interventions in Prodromal Psychosis Safety Issues Chen-Chung Liu • Arsime Demjaha

Springer International Publishing Switzerland 2013

Abstract In recent years, psychopharmacological intervention in prodromal psychosis, also known as the ultrahigh risk (UHR) mental state for psychosis, has attracted much attention. Whilst it has been shown that antipsychotic use in UHR individuals may be effective in potentially delaying or even averting progression to frank psychosis, their use in subjects that do not necessarily convert to psychosis has raised considerable ethical concerns because of their adverse effects. Recent treatment guidelines for patients at UHR for psychosis recommend the use of antipsychotics only in exceptional conditions and with great precautions. To date only a few studies have investigated the use of antipsychotic medications in UHR patients and the potential benefits and risks related to their use in prodromal psychosis remain unclear. We review here all published studies that included UHR patients treated with antipsychotics, regardless of study design. These studies were all of second-generation antipsychotics, given that first-generation antipsychotics cannot be recommended because of their adverse drug reactions. We specifically examine the available descriptions of adverse reactions of the individual antipsychotic medication in each study and discuss the potential effects of various demographic and clinical factors that may impact on safety issues of pharmacological interventions in UHR patients. Clinical trials to date investigating potential benefits of antipsychotic C.-C. Liu (&) Department of Psychiatry, National Taiwan University Hospital and College of Medicine, No. 7 Chung Shan S. Rd, Taipei 10002, Taiwan e-mail: [email protected] A. Demjaha Department of Psychosis Studies, Institute of Psychiatry, King’s College London, London, UK

treatments in preventing transition to psychosis were of relatively short duration and have involved a small number of patients. Whilst it appears that pharmacological intervention at this stage may be effective in both reducing the psychopathology and decreasing transition rates, and is potentially safe, in the absence of sufficient evidence-based knowledge to guide treatment, definitive clinical recommendations and guidelines cannot be derived. Certain adverse events take time to develop, such as metabolic syndrome and endocrine-related effects, thus longer term clinical trials with a larger number of patients are needed to determine the effectiveness of antipsychotic intervention and the relationship of its duration to emergence of adverse events. This can inform the development of timely strategies to prevent serious negative impacts and thus maximize the benefits of antipsychotic intervention in UHR patients that outweigh the risks associated with their use.

1 Introduction Over the last 2 decades, the prodromal phase of psychosis has become a major focus of both clinical work and research, which led to the development of early intervention services, intended to delay or avert the progression to schizophrenia and other psychotic disorders [1–4] (for an updated critical review, see Fusar-Poli et al. [5]). Interest in this area has grown to the extent that a new diagnostic category, attenuated psychosis syndrome, is being considered for inclusion in the forthcoming DSM-5 [6]. The availability of second-generation antipsychotics (SGA) that are less likely than first-generation antipsychotics (FGA) to produce extrapyramidal side effects (EPSE) and hyperprolactinaemia has made antipsychotic treatment for patients distressed by their recently emerged or aggravated

Author's personal copy C. Liu, A. Demjaha

subthreshold psychotic symptoms, namely prodromal psychosis, prior to the onset of full-blown psychosis more ethically acceptable [7]. In the past 15 years, youth presenting with attenuated psychotic symptoms or brief, limited, intermittent psychotic symptoms were operationally defined as clinically at ultra-high risk (UHR) for psychosis to test the effectiveness of early interventions [3]. Because a true ‘prodrome’ of psychosis can only be confirmed retrospectively after frank psychosis is developed, the UHR state became a preferable term to describe prodromal psychosis (while in this paper we use both terms interchangeably). Several trials using clinical criteria similar to the UHR criteria have demonstrated that initiating antipsychotic treatment at this state can delay the onset of frank psychosis, ameliorate subthreshold psychotic symptoms and improve functioning [3, 8–10]. However, concerns have been raised around safety issues of using antipsychotic medication in UHR subjects, particularly in view of increasing liberal off-label prescribing in this population [11]. Such concerns are accentuated by the high false-positive prediction rates [12], a trend of declining transition rates in areas with well developed early intervention systems [13], high remission rates from an initial UHR state [14, 15] and negative ramifications in terms of ethical issues and stigmatization [16–18]. Thus, it is considered that administering antipsychotic medication to UHR subjects, whilst some of them may never develop frank psychosis, exposes them to unnecessary and unjustifiable risks, and psychological interventions have been suggested as a first-line treatment in UHR subjects. In the recommendations of the second edition of the Australian Clinical Guidelines for early psychosis [19], omega-3 fatty acids, psychological treatment, including cognitive behavioural therapy (CBT) and supportive counselling, and pharmacotherapy for co-morbid psychiatric disorders such as depression are recommended over antipsychotic medications for URH subjects; it is explicitly stated: ‘‘antipsychotic medications should not be considered as the first treatment option for UHR. However, if rapid worsening of psychotic symptoms occurs and is associated with significant deterioration in functioning, and increased risk to self or others, a low-dose atypical antipsychotic may be considered, in conjunction with close monitoring and support.’’ Similar statements were provided in the British Association for Psychopharmacology recommendations [20]: if antipsychotic medication is considered for symptom alleviation in the prodromal phase of psychosis, (1) this should be treated as off-label prescribing, (2) the prescription should be short-term, (3) very low doses should be used, (4) symptom response should be monitored, (5) side effects should be carefully monitored and (6) it should be prescribed by specialist psychiatric

services, such as an early intervention team. Whilst these two guidelines were based on limited evidence, we think a balanced clinical judgement on the safety issues with reference to its potential benefits might be appropriate to optimize the utility of antipsychotic medications in treating prodromal psychosis. Retrieving the original reports of antipsychotic interventions for prodromal psychosis from the reference lists of the afore-mentioned two guidelines and the latest Cochrane review of early intervention for prodromal psychosis [19– 21], we found only a few randomized controlled trials (RCTs) have been performed; most of them involved small samples, and not all studies provided detailed reports of adverse effects. We therefore searched on PubMed using the search terms ‘ultra high risk’, ‘prodrome’, ‘prodromal psychosis’, ‘antipsychotic’ and ‘acute treatment’ to include all published studies that have treated UHR subjects with antipsychotics and provided information of safety issues that could be inferred to individual antipsychotic medication. One recently accepted manuscript of the first author (CCL) was also added. We specifically examined the available descriptions of adverse reactions in each study to allow us to discuss the potential effects of various demographic and clinical factors that may impact on safety issues of pharmacological interventions in prodromal psychosis. We also highlight recent neurobiological findings that are relevant to potential effects and adverse effects while using antipsychotic intervention in prodromal psychosis to provide an insightful look into this issue.

2 Rationale for Using Antipsychotic Intervention in Prodromal Psychosis It is recognized that regardless of whether help-seeking subjects with putative prodromal psychosis are going to convert to frank psychosis or not, they are distressed, ill and deserve clinical attention [22, 23]. As most subjects at UHR for psychosis have attenuated psychotic symptoms similar in quality to those observed in schizophrenic spectrum disorders [24], as an extrapolation, antipsychotic treatment seems to be a rational treatment strategy for this group of patients [25, 26]. 2.1 The Risk of Transition to Psychosis in Patients at High-Risk State A recent meta-analysis involving 2,502 UHR patients revealed that overall the mean transition risk to a full psychotic episode from an UHR state was 29.2 % (95 % CI, 27.3–31.1), with a mean follow-up of 31 months. The transition risks at 6, 12, 18, 24, 36 and more than 36 months were 17.7 %, 21.7 %, 26.9 %, 29.1 %, 31.5 %

Author's personal copy Safety of Antipsychotic Use in Prodromal Psychosis

and 35.8 %, respectively [27]. This constitutes a substantial proportion of subjects who are at imminent risk of progressing to a devastating mental illness. Additionally, most of the subjects who will later transition to psychosis will develop a schizophrenia spectrum psychotic disorder [28].

antipsychotic medications. However, to date, no reliable neurofunctional, structural or neurochemical marker of an impending psychosis has been established for clinical use [47, 48].

2.2 The Risk of Transition to Psychosis: Comparison Between Antipsychotic- and Non-AntipsychoticTreated Ultra-High Risk (UHR) Subjects

3 Concerns About Safety Issues for Antipsychotic Intervention in Prodromal Psychosis

In a subset of the same meta-analysis, the transition risk in UHR patients who had received antipsychotics was 22.9 % (95 % CI, 20.5–25.5), which is significantly lower than the risk in those who had not received antipsychotics (36.5 %; 95 % CI, 32.1–41.3) [p \ 0.001] [27]. Apart from demonstrating an apparent advantage of antipsychotic treatment in decreasing the transition rates, this meta-analysis also showed that patients receiving some specific form of psychological treatment had lower transition rates (24.9 %; 95 % CI, 23.2–28.0) compared with those who received usual care (32.8 %; 95 % CI, 29.5–36.2) [p = 0.001]. This indicates that antipsychotic medication is not the only intervention that could prevent transition to psychosis. 2.3 Neurobiological Evidence At a neuroscientific level, the proposed framework of ‘‘dopamine-related increased aberrant salience’’ [29] suggests that administering antipsychotic medication at a putative psychotic prodrome to create a ‘‘sense of detachment’’ can facilitate the individual to attenuate their overreactions to salience, and ultimately prevent progression to psychosis. Evidence for potential effectiveness of antipsychotics in prodromal psychosis comes from recent imaging studies that have demonstrated neurofunctional [30, 31], neuroanatomical [32, 33], dopaminergic [34–37] and glutamatergic [38] abnormalities in UHR subjects compared with healthy controls and patients with firstepisode schizophrenia [39–41]. These alterations are associated with subtle but significant impairments in cognitive functioning [42]. It was shown that not only is the grey matter reduced in UHR subjects [40], but this abnormality increases longitudinally as these subjects progress to developing psychosis [43, 44]. Analogously, F-DOPA PET studies have demonstrated that presynaptic hyperdopaminergia is present in subjects who are at risk of psychosis, and that it progresses with time in those who have transitioned to a psychotic disorder [39, 45, 46]. These new findings confirm that important neurobiological alterations predate the onset to psychosis, that they are of a dynamic progressive nature, and consequently provide neurobiological evidence for the use of agents impacting the neural underpinnings of psychosis risk, such as

Concerns about the safety issues regarding the use of antipsychotic treatment in UHR patients were derived from limited evidence. FGAs were not considered for treating UHR subjects due to their well established adverse drug reaction (ADR) profile. Indeed, it would be illegitimate to expose subjects who might never develop psychosis to such a treatment. On the other hand, SGAs although with a much lower propensity to cause EPSE, are not adverse effect free, as akathisia, QT interval prolongation and prolactin-related adverse effects are not uncommon in first-episode schizophrenic patients. Also, SGAs have a different ADR profile characterized by weight gain and metabolic disturbances. Theoretically, patients at a putatively psychotic prodrome might respond to lower doses of antipsychotic medication and hopefully a lower dosage will cause fewer adverse reactions; however, patients with prodromal psychosis might also be more sensitive to ADR than those with established illness. Empirically, only limited observations to date can provide information to delineate these concerns. We first examined the ADR profiles of each individual SGA that has been used for treating UHR patients (Table 1), including two RCTs using risperidone, two RCTs using olanzapine, one open-label randomized parallel-group trial using amisulpride and four open-label single-arm trials using aripiprazole; while no studies using other SGAs (such as quetiapine and ziprasidone) for prodromal psychosis have been published to the date of this review. We then explored the variables that might modulate this hypothetical risk and benefit scale for assessing the feasibility of antipsychotic interventions in UHR individuals. 3.1 Adverse Events of Individual Antipsychotics in UHR Studies 3.1.1 Risperidone In the RCT by McGorry et al., only one patient reported ‘‘minor rigidity’’, and three patients complained of mild sedation [8]. In all four cases these effects were reversed by dose reduction. In the study by Yung et al. [49], using the Udvalg for Kliniske Undersogelser (UKU) adverse effect rating scale, UHR patients treated with risperidone showed no significant difference in the frequencies of adverse

Author's personal copy C. Liu, A. Demjaha Table 1 Summarized characteristics of reviewed studies Dosage (mg/day)

Duration of treatment

Comments on AP treatment response

AEs related to APa

1–2

6 months

Lower rates of transition to psychosis

Mild rigidity and mild sedation

8 weeks

Improved prodromal psychopathology

One dropout due to AE; body weight gain and increased sitting pulse

5–15

12 months


Much more weight gain and fatigue

50–800

12 weeks

Improved psychopathology/ improved global functioning

Three dropouts due to AEs; elevated prolactin-related AEs, fatigue, sleep problems and sweating, weight gain

8 weeks

Improved prodromal psychopathology/ improved neuropsychological functioning

One dropout due to AE; sedation, akathisia, irritability, increased appetite, sedation, insomnia, nervousness, impaired memory, impaired sensory perception, hypersalivation, decreased libido and excessive sweating

Endpoint mean ± SD: 10.7 ± 5.4

8 weeks

Improved prodromal psychopathology and insight

Two withdrawals due to AEs; akathisia, irritability and headache

Aripiprazole

2–7.5

1 week


Headache, sedation, restlessness, leg pain, dizziness, poor appetite and blurred vision

Risperidone

0.5–2

6 months

No significant difference in rates of transition to psychosis among three groups

No significant difference among three groups; possibly risperidone-related weight gain

Aripiprazole

3.75–7.5

4 weeks


Headache, sedation, restlessness, insomnia, weakness and indigestion

Study (year)

Study design

Number of patients

AP

McGorry et al. [8] (2002)

Randomized controlled

n = 31 (AP)

Risperidone

Woods et al. [10] (2003)


n = 31 (AP)

McGlashan et al. [50] (2006)


n = 31 (AP)

Ruhrmann et al. [9] (2007)

Open-label randomized, parallelgroup

n = 58 (AP)

Woods et al. [51] (2007)

Open-label

n = 15 (AP)

Kobayashi et al. [52] (2009)

Open-label

n = 36 (AP)

Aripiprazole

Liu et al. [53] (2010)

Open-label

n = 9 (AP)

Yung et al. [49] (2011)


n = 43 (AP ? CT)

n = 28 (NBT)

Mean ± SD: 1.3 ± 0.9 Olanzapine

n = 29 (NBT)

5–15 Mean ± SD: 8.0 ± 3.1

Olanzapine

n = 29 (NBT) Amisulpride

n = 59 (NBT)

Endpoint mean ± SD: 169.5 ± 18.5

Aripiprazole

5–30 Mean ± SD: 15 ± 7

n = 44 (placebo ? CT) n = 28 (placebo ? ST)

Liu et al. [54] (2013)

Open-label

n = 11 (AP)

AEs adverse events, AP antipsychotic, CT cognitive therapy, NBT needs-based treatment without AP, ST supportive therapy a

AEs summarized here are those that appeared significantly more frequently in the AP-treated group in comparison studies or those that were reported by more than 10 % of AP-treated participants in open-label studies


events between their baseline and 6-month follow-up reports, nor was there any significant difference found between the risperidone-treated group and the other two groups who did not receive antipsychotic treatment. A larger proportion of the risperidone-treated group had an increase in weight (30.0 % vs. 9.1 % and 6.7 %), but this was not statistically significant. 3.1.2 Olanzapine Studies of olanzapine treatment have raised the greatest concerns regarding the dilemma between efficacy and adverse events. The dose of olanzapine used in these studies is at the lower limit of common recommendations for treating patients with schizophrenia, but still associated with significant weight gain. The report by Wood et al. of their short-term, doubleblind, RCT revealed a significant increase in body weight (4.5 ± 6.6 kg, p = 0.001) and sitting pulse (10.7 ± 15.8 bpm, p = 0.042) [10]. Specifically, 56.7 % of the olanzapine group gained more than 7 % of their baseline body weight versus 3.4 % of the placebo group (p \ 0.001). Patients in the olanzapine group subjectively complained more about their weight gain and one patient discontinued treatment secondary to this adverse effect. There were no significant differences in measurements of involuntary movement between groups, and the groups did not differ in terms of concomitant use of benzodiazepines or anticholinergic agents. The report by McGlashan et al. also showed marked weight gain by the end of the 1-year follow-up (8.79 ± 9.05 kg vs. 0.30 ± 4.24 kg, p \ 0.001), with 61.3 % of the olanzapine group versus 17.2 % of the placebo group gaining more than 7 % of their baseline body weight (p = 0.001) [50]. Additionally, fatigue was more frequently reported by the olanzapine-treated group (29.0 % vs. 3.4 %, p = 0.01). 3.1.3 Amisulpride The short-term trial by Ruhrmann et al. reported that prolactin-associated symptoms were the main adverse effects that resulted in three patients dropping out of the study: two with galactorrhea and one with sexual dysfunction [9]. Prolactin levels increased more frequently in the amisulpride-treated group (81.8 % vs. 20.6 %; p \ 0.001) with a considerable increase from baseline to the end-point of the study (amisulpride group 795.4 % vs. 47.2 % in the group that did not receive amisulpride; p \ 0.001). Also, a much larger proportion in the amisulpride group (75.2 %) had end-point prolactin levels exceeding more than twice the upper limit of normal range compared with the controls (3.2 %) [p \ 0.001]. A substantial proportion of

amisulpride-treated female patients were classified as having more possible or probable prolactin-related adverse events by using the UKU adverse effect scale, such as menstrual disorders, galactorrhea and breast tenderness/ swelling. Both male and female amisulpride-treated subjects also reported fatigue, sleep problems, increased sweating and weight gain more frequently. On the other hand, only higher ratings of akathisia in the amisulpridetreated group, while no significant differences in EPSE subscales of parkinsonism, dyskinesia and dystonia were observed between groups; the body mass index (BMI) increased significantly in the amisulpride group with a mean gain of 0.63 kg/m2 (2.6 %) from baseline. 3.1.4 Aripiprazole To date no RCTs investigating aripiprazole use in the UHR group have been performed. The open-label pilot study by Woods et al. reported one patient discontinued due to sedation while eight experienced treatment-associated akathisia, which were generally manageable by adding an anticholinergic agent or benzodiazepine and/or reducing dose titration, and mostly were tolerable throughout the 8-week treatment [51]. Participants’ reports to Systematic Assessment for Treatment Emergent Events (SAFTEE) revealed quite a few symptoms as listed in Table 1. No significant increase in involuntary movement and body weight was observed although average body weight gain was 1.2 kg after 8 weeks of treatment. The study by Kobayashi et al. of a Japanese population reported that two patients discontinued due to adverse events (these are not specified), four experienced treatment-emergent akathisia, which was reported to be mild and manageable, as well as other treatment-emergent adverse effects as listed in Table 1 [52]. Liu et al. reported two small-scale series of clinical observations using a very low dosage in a Taiwanese population [53, 54]. Almost all patients reported at least one treatment-emergent adverse event during this short treatment period with only one patient not reporting any adverse reactions. 3.2 Potential Variables to Modulate the Estimate of Risks 3.2.1 The Role of Age, Gender and Ethnicity A recent meta-analysis by Fusar-Poli et al. [27] revealed that increasing age of patients at UHR is significantly correlated to increased risks for psychosis. In terms of safety, a study by Woods et al. [55] found that more sedation and weight gain were reported in children and adolescents than in adult patients. This suggests that for


help-seeking subjects at UHR for psychosis who are in their late 20s, olanzapine may be more beneficial than for their teenager counterparts. Similarly, gender should be taken into account while amisulpride is used as more prolactin-related effects in women were noticed. Also, ethnicity may explain the high frequency of adverse events in Taiwanese and Japanese studies even with very low doses of aripiprazole [53, 54, 56].

trials might be those who were tolerating medication better. It is also possible that during a longer course of treatment adverse events have lessened or been managed by either slowing down titration, or providing concomitant medication for temporary symptom relief. Additionally, there is recent concern for a grey matter loss with long-term antipsychotic treatment in patients with schizophrenia, after controlling for duration of illness, illness severity and other factors [59, 60].

3.2.2 The Role of Drug Naivety 3.2.4 The Role of Concomitant Medications The majority of UHR patients in these studies have never had previous exposure to antipsychotic treatment. Theoretically, being drug naive may predispose them to greater sensitivity to antipsychotic medications. However, since this issue was not specifically addressed in most studies, the impact of drug naivety on sensitivity to and intensity of adverse effects remains unclear. In a study by Takahashi et al. [57] that investigated drug-naive first-episode schizophrenic patients treated with aripiprazole (17.8 ± 9.5 mg/day), high rates of frequencies of restlessness (40.5 %) and headaches (14.3 %) were reported. Moreover, two other studies of drug-naive UHR patients also reported high frequency of irritability and nervousness, but surprisingly observed higher rates of sedation/somnolence rather than insomnia, that may be possibly attributable to drug-naivety status [52–54]. The severity and frequency of adverse events, on the other hand, was much lower in studies of schizophrenic patients experiencing acute relapse during the early stage of their illness (i.e., not drug naı¨ve) who were treated with aripiprazole [58]. 3.2.3 The Dosage and Duration of Antipsychotic Intervention The UHR studies reveal that the dosages of antipsychotic medications are generally much lower than those used for treating first-episode psychosis patients, suggesting that UHR patients are more susceptible to adverse events. However, weight gain was not found to be correlated with the dose of olanzapine [10] and, similarly, prolactin-related adverse events were not related to the dose of amisulpride [9]. In the case of aripiprazole, it remains unclear whether its unique pharmacological mechanisms at a relatively lower dosage may be accountable for the adverse reactions reported or whether these may be due to an interaction between pharmacodynamic mechanisms and ethnicity. Interestingly, higher frequencies of treatment-emergent adverse events were reported in clinical trials lasting no longer than 12 weeks, compared with the longer-term risperidone studies. Patients who experienced adverse events might have either been non-compliant or have simply dropped out, while those who were retained in clinical

Ruhrmann et al. specifically examined whether the extent of amisulpride-related prolactin elevation would be affected by concomitant use of selective serotonin re-uptake inhibitors (SSRIs) and demonstrated that the mean values in both male and female patients who received both amisulpride and an SSRI were more than twice that in those who only received amisulpride [9]. This illustrates that there are many factors such as polypharmacy that might contribute to the emergence of adverse effects and consequently lead to poor long-term outcomes [11]. 3.2.5 Reversibility of Adverse Events McGlashan et al. demonstrated that after active treatment with olanzapine for 1 year, nine of their original 30 olanzapine-treated patients with significant weight gain during the treatment period who received an extended no-treatment 1-year follow-up had their body weight significantly decreased (-6.46 ± 5.32 kg) [50]. This finding suggests that although weight gain is a remarkable adverse reaction, it is possible to reverse it once medication is discontinued. Similarly, amisulpride-related endocrine/sexual adverse reactions are supposed to be reversible once amisulpride has been discontinued for a certain period of time, and we need to observe how long it will take and to what extent the subject can recover from these adverse events.

4 Discussion The concerns about negative impacts of antipsychotic intervention in UHR individuals seem to outweigh its potential benefits as revealed in two treatment guidelines. The recommendations of the second edition of the Australian Clinical Guidelines for the treatment of UHR patients emphasize the seriousness of imprudent use of antipsychotics and limit the use of these drugs in the UHR state to ‘‘exceptional’’ circumstances. The guidelines of the British Association for Psychopharmacology also recommend caution with the use of antipsychotics – ‘‘very low-dose antipsychotic medication can be considered for


short-term symptom relief, although such a prescription would be ‘off-label’ in terms of indication and there are only limited trial data to inform dosage …’’. Such a ‘symptomatic’ treatment approach implies that using antipsychotics in prodromal psychosis is not well supported by current knowledge, and thus a conservative stance should be taken. Nevertheless, we would like to scrutinize the rationales of antipsychotic intervention in prodromal psychosis again and try to find ways, not at the expense of increasing risks, to make antipsychotics more feasible than the aforementioned guidelines. It seems obvious that antipsychotic intervention is effective in reducing transition rates and improving prodromal psychopathology. Neurobiological findings provide reasonable mechanisms to support such a pharmacological approach. Available clinical trials suggest short-term and low-dose antipsychotic medications can impact the presenting symptoms and later psychosis onset, although its long-term impact is not yet established. In the detailed examination of available data, many of the adverse events of each SGA seemed to be benign, tolerable and manageable, especially if it is prescribed at a low dose in a short-term trial and takes into account the variables related to the individual SGA’s special features. Moreover, antipsychotic medication might be able to additionally facilitate psychological treatment and exert synergistic effects for early intervention from the pre-psychotic state, although so far only one study has dealt with this intriguing question and is limited by the low participation rates and the low transition rates [49]. However, when trying to adopt antipsychotic intervention in prodromal psychosis, there are a few important issues to consider. First, patients should be informed that the use of antipsychotics is for ameliorating their current distress and impairment [23], and that it does not necessarily imply that they will eventually develop frank psychosis if they do not take antipsychotics, as a substantial proportion of UHR subjects are remitted during follow-up without being administered any antipsychotic [61, 62]. Second, a lower dosage does not guarantee fewer ADRs as treatment-emergent adverse events are frequently seen at a dosage much lower than that for treating full-blown psychosis. Third, some patients with early ADRs might hold a negative attitude toward antipsychotic treatment due to these first treatment-emergent unpleasant experiences. For those who develop frank psychosis later on, their compliance to medication would be discouraged if their negative impression towards antipsychotics is not appropriately solved. Fourth, certain ADRs take time to develop, such as metabolic syndrome, endocrine-related effects and even detrimental impact to brain structure. Fifth, certain ADRs are more likely to occur in patients with certain clinical and demographic characteristics, such as concomitant medication, age or gender. Sixth, if an ADR occurs, it will be

better to lower the dosage or discontinue the use of antipsychotics at first, re-evaluate the risks and benefits of antipsychotics, discuss the advantages and disadvantages with the patients and closely monitor the ADR whether it is discontinued or not. Seventh, a rapid and good response to short-term antipsychotic intervention might undermine patients’ compliance when they need to take it regularly if they transit to full-blown schizophrenia a few years later. Thus, psychoeducation regarding the distinction between the rationales of antipsychotic treatment in the UHR state and frank schizophrenia should be carefully provided. Indeed, one of the most serious safety issues of concern is not the antipsychotics per se, but the non-specialist’s injudicious off-label prescription of antipsychotics. As the reliability of the proposed ‘attenuated psychosis syndrome’ has not yet been established in clinical practice and the concern that in application the boundaries of the definition may be broadened from that designated in criteria [63], a very low-dose short-term antipsychotic intervention for symptomatic treatment should not be treated as a convenient option for UHR patients unless it is used with discretion and provided with appropriate precaution, monitoring and education.

5 Conclusion In this paper we reviewed both clinical and neurobiological evidence referring to the justification of antipsychotic interventions in prodromal psychosis. We also examined the treatment-emergent adverse events in detail and tried to identify solutions to lower such risks. Although the potential positive impact of antipsychotic intervention is enticing, the concerns about safety issues still prevent us from recommending antipsychotic treatment in UHR subjects as first-line therapy to non-specialists. In light of sparse and limited evidence, more studies investigating those clinical and demographic factors and their relationship to antipsychotic adverse effects are needed before we can derive evidence-based management strategies for UHR patients. In view of the lack of evidence for safe and effective treatments, the safer approaches should be preferred. These include psychological interventions such as CBT and potential neuroprotective agents (such as fish oil). Antipsychotics should be reserved for UHR individuals who do not respond to these interventions or who are on the line towards an imminent transition to disease as suggested by the second edition of the Australian Clinical Guidelines and the guidelines proposed by the British Association for Psychopharmacology. Nonetheless, antipsychotic medications might have a more active role in early intervention for prodromal


psychosis as long as appropriate and sufficient instructions, precautions, monitoring and education have been provided to both psychiatrists and UHR patients. Future research should focus on patients who have failed to ‘remit’ from the UHR state with psychosocial interventions alone and who are still distressed and functionally impaired. Longer term clinical trials with a larger number of patients are needed to determine the effectiveness of antipsychotic intervention and the relationship of its duration to emergence of adverse events and to help us to develop timely strategies to prevent serious negative impacts. Future research in the field is urgently needed by taking into account the variables discussed in this review to develop a safer strategy of commencing a low medication dose with carefully designed individualized treatment. Acknowledgements This work was proposed by Dr. Paolo FusarPoli and done by Dr. Chen-Chung Liu’s visit at the Orygen Youth Health (OYH) Research Center in Melbourne, Australia. The authors appreciate Dr. Fusar-Poli’s guidance and the critical and informative comments provided by the OYH researchers and psychiatrists. Dr. Chen-Chung Liu has received payments for lectures at companysponsored symposia provided by Astra-Zeneca, Janssen-Cilag, Otsuka and Pfizer. These payments had no role in the preparation of this manuscript. Dr. Demjaha has no conflicts of interest to declare.

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