Rapid response to antipsychotic treatment on psychotic prodrome: Implications from a case series
*Chen-Chung Liu, MD PhD, Department of Psychiatry, National Taiwan University Hospital, No. 7 Chung Shan S. Road, Taipei 10002, Taiwan. Email: firstname.lastname@example.org
The feasible intervention strategy at the prodromal state of psychosis is under debate. We report nine subjects clinically in a putative prodromal state of psychosis who responded to low-dose aripiprazole within the first week of medication. We conjecture that the pathophysiological processes might be easier to modify by antipsychotics in the prodromal state and we believe a short-term low-dose trial of antipsychotic agents is a convenient option for subjects at ultra high risk of psychosis. We urge specific attention to monitor the dissolution of psychotic-like symptoms carefully in order to have a better understanding of the pathogenesis and pharmacotherapy in the inception of psychosis.
THE PRODROMAL STATE of psychosis has become the focus of interest in recent decades because early intervention is expected to delay or abort the onset of schizophrenia.1–5 Initiating antipsychotic treatment in this state has been demonstrated to decrease the conversion rates in several randomized control studies,2,6,7 but whether the benefits of early pharmacological intervention can outweigh its potential hazards is still debatable. Ethical considerations regarding the false positive identification of suspected prodromal subjects and the adverse reactions related to pharmacotherapy should never be overlooked,8,9 especially considering that the conversion rate declined in a recent cohort, which challenges the necessity of antipsychotic treatment.10,11
Such a clinical dilemma might be mitigated by having a greater understanding of the mechanisms regarding the formation of psychotic symptoms. Howes et al. has found that striatal dopamine overactivity is common in subjects with prodromal psychotic symptoms.12 Such a neurochemical abnormality might be the final common pathway of complex underlying pathophysiological processes.13 In the theory presented by Kapur et al.,14 the dopamine-related increased aberrant salience will lead to a sense of perplexity and confusion and result in mood and behavioral changes, while the formation of delusion or hallucination is the individual's effort to make sense of these seemingly unusual yet irresistible experiences. Therefore a ‘sense of detachment’ caused by antipsychotic agents can enable the individual to attenuate their overreactions to salience and hopefully can prevent the progression into psychosis. Consequently, regardless of true or false identification of a suspected prodromal state, a short-term trial of antipsychotic treatment will be a convenient option to deter the inception of full-blown psychosis, regardless of whether the subthreshold psychotic symptoms would be transient or progressive if not being treated.
The introduction of second-generation antipsychotics might prompt psychiatrists to initiate pharmacotherapy for their better adverse reactions profile, although a study has shown marked bodyweight-gain in prodromal subjects treated with olanzapine.7 Aripiprazole, an antipsychotic agent with novel pharmacological mechanisms, could be the safer agent for fewer adverse effects.15,16 In our preliminary works between January 2007 and September 2008 at the special clinic for subjects at high risk of psychosis,17 we tested aripiprazole on 13 ultra high-risk subjects for tolerability and we were impressed by their rapid response. Here we present our clinical observations in detail and propose our inferences.
This is a naturalistic observation, as part of the prospective study on the psychopathological progress of the prepsychotic state (SOPRES) in Taiwan, on 13 subjects, eight female and five male subjects, diagnosed in a putative prodromal state of psychosis treated by aripiprazole at the outpatient clinic of the study hospital.17 The SOPRES has been approved by the Institutional Review Board of the study hospital. All subjects fulfilled the criteria designated by comprehensive assessment of at-risk mental status (CAARMS),1 either as the attenuated psychotic symptoms (APS) group (n = 8) or the brief limited intermittent psychotic symptoms (BLIPS) group (n = 5). None of the subjects fulfilled the criteria of any psychotic disorder or substance abuse in the DMS-IV. Twelve of the 13 subjects were drug-naïve prior to this treatment. Only one subject had been treated with low-dose quetiapine (100 mg/day) for a few weeks. The initial daily dosage of aripiprazole was from 2 to 7.5 mg. A 0.5-mg dose of lorazepam was given to some patients for as-needed use, but only one patient used it at the beginning of the treatment and then she opted to stay on aripiprazole only.
The first two patients in this series (Case 1 and Case 6) returned earlier than their scheduled one-week visit due to some adverse reactions; however they also reported remarkable improvement, so in later practice, at the first one-week follow-up visit we asked all patients to thoroughly describe when they started to experience a significant response. The details of their clinical presentations and treatment responses were documented qualitatively rather than quantitatively because we interpreted their descriptions as extremely impressive and important, and these details would be overlooked if monitored by weekly rating scales. Ten of the 13 subjects reported rapid response, namely a much-improved status reached within the first week of treatment; however one of these 10 did not return after her second visit; one of the other three subjects did not show up after his first visit, and the remaining two achieved a much-improved status 6–8 weeks later. In this paper we focus on the nine prodromal subjects with rapid response to aripiprazole who received follow up for 9–27 months.
Table 1 is the summary of the nine subjects, seven female and two male subjects, aged between 13 and 29 years old, clinically manifested either as the APS group (Cases 1, 4, 5, 7, 9) or the BLIPS group (Cases 2, 3, 6, 8). Five of the nine experienced considerable amelioration of their main clinical manifestations (as detailed in Table 1) after the first one or two administrations. Here are a few simulated narratives about their initial responses:
Table 1. Summary of case descriptions
|1||17||M||Excessive rumination about resentful scenes and feelings, suspiciousness and hostility, mild idea of reference, vague and transient auditory/visual hallucination||6 months||3.75 mg||1–2 days||Restlessness||24 months|
|2||13||F||Idea of reference, felt she was being followed, brief intermittent auditory hallucination||3 weeks||3.75 mg||1–2 days||Headache||13 months|
|3||20||F||Pseudo hallucination (commenting on her thoughts), suspiciousness, sensitive to and felt hostility from male acquaintances, idea of reference and being monitored||1 month||7.5 mg||1–2 days||Sedation||9 months|
|4||19||F||Intense ‘internal conflicts’ between ‘two selves’, difficult to express how she felt, fear of losing control, overwhelmed by extreme anxiety, derealization||12 months||7.5 mg||1–2 days||Headache||20 months|
|5||22||F||Hypervigilance, suspiciousness, emotional turmoil, vague sense of her thoughts being known by others, idea of reference, transient auditory hallucinations and illusions||3 months||3.75 mg||1–2 days||Headache||9 months|
|6||17||F||Feeling of being watched, fear of being monitored, idea of reference, vague persecutory ideations, emotional turmoil||1 week||7.5 mg||3–5 days||Sedation||27 months|
|7||17||M||Odd behaviors, peculiar smiling and self-murmuring, telepathy, magic thinking, peculiar somatic complaints, referential and persecutory ideations||2 months||3.75 mg||3–5 days||Dizziness, blurred vision||17 months|
|8||14||F||Idea of reference, interpersonal oversensitivity, compulsive washing, felt she was being followed, brief limited auditory and visual hallucinations||3 weeks||2 mg||5–7 days||Drowsiness, poor appetite||16 months|
|9||29||F||Felt insecure, vague feeling of being followed, exaggerated emotional reactions to ordinary life events, frequent verbal aggression, circumstantial speech||12 months||3.75 mg||5–7 days||Headache, leg pain||24 months|
Case 1: My rumination just decreased to a great extent the first day I took the medicine . . . , now I can sit down to study without distraction by those resentful feelings and scenes that used to preoccupy my mind. . . .
Case 3: I felt calm, not so sensitive or suspicious, and much less confused after taking the medicine . . . ; its effect was most prominent at the first two doses and continued working in the following days.
The other four also had marked decreases in frequency, duration, or severity of their psychotic-like symptoms within 3–7 days.
Case 6: After much better sleep for three or four days, my previous fear was gone and I don't know why I would think in that way (idea of reference and persecutory ideations). Sometimes I am still sensitive to phone calls or certain messages from the television, but I have no problem to shift attention to my parents' companionship and support.
During the follow up, Case 1 and Case 7 intermittently used 2–3.75 mg and maintained a much-improved condition. Case 2 and Case 8 discontinued medications within 2 months and stayed well in a drug-free condition during follow up. Case 3 halved the dosage soon after a good initial response but her symptoms were aggravated to audible thoughts and true hallucinations later. She opted to take 15 mg/day in order to remain symptom-free as she had a family history of schizophrenia. Case 4 slowly progressed into true auditory hallucination with minimal interference to her daily life. She opted to maintain a 7.5-mg/day dose. Case 5 experienced persistent drug-related headache so we shifted to amisulpiride. She used just 100 mg/day intermittently for her protracted APS despite the recommendation to use it regularly. Case 6 gradually tapered off the medicine over 18 months, was well for another 6 months, yet then developed a brief psychotic episode, which responded to reinstitution of aripiprazole within 2 weeks. Case 9 tapered off smoothly over 6 months, was lost to follow up for the next 18 months, then came back presenting full-blown paranoid schizophrenia features, which have lasted for more than 3 months.
Our subjects responded much faster under even lower dosage of aripiprazole compared to previous reports.3,18,19 Four of the nine subjects had full-blown psychosis later on and one had persistent attenuated psychotic syndrome; this suggests that our identification of ultra high-risk subjects is stringent and their early response is likely to be genuine. It might be the result of an ethnicity-related slower drug metabolism rate, but previously a randomized control study using 15 mg/day aripiprazole in Chinese schizophrenic patients did not show an early response pattern.20
The rapid effect on our subjects' subthreshold psychotic symptoms is encouraging. Traditionally the onset of therapeutic action on full-blown psychosis is expected to be 2–3 weeks after the initiation of antipsychotics. However, the review by Agid et al. suggested that the onset of antipsychotic effects is most pronounced within one week,21 and Kapur et al. demonstrated that the onset could be within the first 24 h.22 Thus it is reasonable to expect an earlier response in prodromal subjects. If the pathophysiological processes at the prodromal state were easier to reverse than that of the full-blown psychotic state, initiation of antipsychotic treatment at this stage should be encouraged. Even though psychosocial intervention, cognitive therapy, and even antidepressants might be as effective for preventing conversion into full-blown psychosis,5,23 the antipsychotic should have its role. Indeed the non-pharmacotherapeutic measures could be delivered easily once the prodromal subject's ‘dopamine-mediated aberrant salience’ is attenuated,14 and a recent study has demonstrated that not only the prodromal symptoms but also the patient's insight and subjective well-being were improved by aripiprazole treatment.19 Once an initial rapid response is achieved, the at-risk individuals can be taught to identify signals of psychotic prodrome; they can learn how to cope with quasi-psychotic experiences; and they can understand the benefits of medications. Hopefully such an integrated biopsychosocial approach will be a feasible regimen to modify and even deter the trajectory of psychosis formation.
The rapid response might not be exclusive to aripiprazole, although its unique mechanisms on dopamine receptor, the D2 partial agonist24 and the fast dissociation phenomenon25 might play a role in such a favorable outcome in our mostly young and drug-naïve prodromal subjects. Indeed we also noticed that risperidone could be effective at around 1 mg/day and amisulpiride could be effective below 200 mg/day in some cases of the SOPRES; while similar to aripiprazole, these medications also caused noticeable adverse reactions, such as sedation, noticeable weight-gain, or amenorrhea at a low dosage. More randomized clinical trials should be carried out to examine the role of the placebo effect and to compare the advantages and disadvantages among different psychotropic agents. Also, we need to monitor the changes in symptoms more frequently than we did in this study in order to minimize recall bias and to confirm the rapid response.
In contrast with previous clinical trials that have demonstrated the benefits of early intervention by decreased conversion rates, this case series is the first study to have such a close look at the phenomena occurring within a few days of antipsychotic treatment in psychotic prodrome. We linked our observations to current pathophysiological and psychopharmacological findings in order to propose an innovative concept for intervention of psychotic prodrome. We urge specific attention to monitor the processes of dissolution of subthreshold psychotic symptoms in order to have a better understanding of the pathogenesis and pharmacotherapy at the inception of psychosis.
The study on the psychopathological progress of the prepsychotic state (SOPRES) is supported by the National Health Research Institutes, Taiwan (NHRI-EX95, 96, 97, 98-9511PP). Chen-Chung Liu's work on descriptive psychopathology is supported by the National Science Council, Taiwan (NSC 97-2511-S-002-007).