Prevention of Psychosis in the Symptomatic Prodromal Phase

Methods/Design

Overall Design

The current study will use a health service design modeled after the TIPS study, using the unique possibilities of the Norwegian catchment area based treatment systems. UHR patients from two areas (the catchment areas of Stavanger and Fonna) will be recruited through information campaigns and assessed by low-threshold detection teams. Recruited individuals will, after giving informed consent, receive structured follow-along by a designated case manager, and receive a multi-modal treatment package containing CBT, family work and Omega-III fatty acids and with the possibility for provision of antipsychotic medication only at imminent risk of conversion. Study personnel blind to treatment allocation will confirm this through a separate symptomatic evaluation.

Information Campaigns and Detection Teams

Each Prodromal Detection and Treatment site will implement a program building upon the combined experiences from the TIPS study and previous prodromal studies, consisting of Information Campaigns (IC) and Low Threshold Detection Teams (DT).^[2] Prodromal detection, like early psychosis detection, requires active outreach and recruitment using information campaigns and specialized detection teams. As demonstrated by the TIPS project, both elements are likely to be critical.^[47] Given that the threshold pathology in the prodrome is likely to be more privately experienced and less publicly apparent, the IC must be intense, persistent, pervasive, and personal. The IC will use three concrete strategies:

Teaching the public about early signs of severe mental illness, the importance of getting help early and the existence of the low threshold DTs;
Provide targeted education programs for teachers and General Practitioner's (GPs) about prodromal symptoms and the content and availability of the PDT program;
Provide targeted education for clinicians in the specialized mental health services to learn them to recognize possible prodromal individuals.

Potential prodromal individuals in the PDT areas will be referred to a DT by health care providers, educators, or social service agencies or they can be self-referrals in response to the IC. Potential subjects will undergo a telephone and/or a face-to-face screen (Prodromal Questionnaire, PQ-B).^[48] Those who screen positive will be invited to an in-person eligibility and consent evaluation based on the SIPS interview.

Prodromal Treatment Package

This will be modeled after practices tried out in the TIPS study as well as practices shown to influence risk of conversion in experimental studies and common to existing prodromal centers. The patients will participate in an individual 2 year follow-along containing the following elements:

One-to-one monitoring of clinical status, symptom levels (prodromal and psychotic), risk profiles (suicidality, dangerousness), instrumental and social functioning;
One-to-one case management to help deal with clinical, familial, social and vocational crises, needs and deficits;
Omega-III fatty acids, in the form of 2g fish oils containing approx. 1.5 g Etyl-Eicosapentaeonic Acid/DHA with 80 mgs Vitamin E per day for 12 weeks;
Individual cognitive behavioral therapy (CBT) to deal with social/cognitive distortions and deficits and to maintain real world investment (based on the EDIE II study).^[49] They will be offered 26 sessions of CBT within a six months period. The CBT sessions will be based on established cognitive models, be collaborative, problem orientated, formulation driven, normalizing, educational and time-limited with Socratic questioning/guided discovery;
Individuals that experience functional loss will in addition receive single-family psycho-education to inform patients and families about current problems, how to understand and cope with them, especially within the family;^[50,51]
Anti-anxiety agents and anti-depressants will be available if the patient is so symptomatic that they otherwise would be prescribed these agents by their GPs;
Antipsychotic medication will be available if the patient either enters the study with any SIPS positive symptom score at the level of 5, or if any positive prodromal symptom score(s) moves from a level of 3 or 4 to a 5. Use will be open labeled based on the patients' current symptom profile. The type and dose of medication will be reviewed by an independent clinical practice safety monitoring board.

Questionnaires and Interviews

Participants will be screened with the Structured Interview for DSM-IV (SCID)^[52]/(Kiddie SADS for adolescents who are 13–17 years old) and the SIPS at study entrance. All participants will be followed with a symptomatic assessment (SIPS) done monthly for the first six months and then every three months for the last two years. The participant will be evaluated by a designated nevopsychological protocol at baseline, 12 and 24 month follow-up and offered to participate in a fMRI substudy. Assessors will not be part of the treatment teams.

Prodromal Inclusion and Exclusion Criteria

Start of study inclusion is from March 1^st 2012, ending inclusion December 31^st 2016.

1) The patient is listed in the national register and residing in the catchment areas of: Stavanger and Fonna; 2) Between 13 and 65 years; 3) Meet diagnostic criteria for prodromal syndrome SIPS criteria;^[11] 4) Does not meet current or life-time criteria for any psychotic disorder; 5) The symptoms are not better accounted for by an axis I, axis II or substance use disorder with the exception of schizotypal personality disorder (the presence of any of these disorders in itself is not an automatic reason for exclusion); 6) Does not use any antipsychotic medication currently and have not used antipsychotic medication (regardless of dosage) for more than four weeks lifetime; 7) No known neurological or endocrine disorders that may have caused the presenting psychotic symptoms; 8) The patient is not mentally retarded with an IQ below 70; 9) The patient must be able to understand and speak Norwegian; 10) The patient must be able to understand and sign an informed consent or assent for minors' document.

Power Calculation

There are no previous studies giving any clear suggestion of the number of high-risk individuals that can be recruited from a well-defined catchment area sample like the current, but previous studies in Melbourne indicate that around 20% of first episode patients have been in contact with the PACE clinic (McGorry, personal communication). Studies up to now give a conservative estimate of a 20% transition rate over the first two years for a non-treated high-risk sample and subsequently a 10% risk in the active treatment group. A power analysis has shown that in order to give an achieved significant reduction of transition rates in the study population with the proposed sample size for the two groups of a) 750 000 with predicted annually detection of 150 first-episode psychosis (FEP) (Bergen and Østfold) and b) 440 000 with annually predicted reduction to 90 FEP (Stavanger and Fonna) through prodromal detection and intervention, the study will have power of 88.9% to yield a statistically significant result.

The Psychosis Incidence Study

The main outcome of the intervention will be the incidence of psychotic disorders in the participating areas. This will be assessed using the same research diagnostic criteria; in all participating areas over all study years.

Incidence Study Inclusion Criteria. 1) The patient is listed in the national register and residing in the catchment areas of Stavanger, Fonna, Bergen, and Østfold; 2) Between 13 and 65 years; 3) Meet diagnostic criteria in DSM-IV for first-episode schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, affective psychoses (Bipolar I disorder, Bipolar II disorder with psychotic symptoms, major depressive disorder with psychotic symptoms) or psychotic disorders NOS; 4) The patient is (or has recently been) active psychotic with symptoms of delusions, hallucinations, disturbed thinking, unsuitable/bizarre behaviour which cannot clearly be explained by organic reasons. The symptoms must have lasted the whole day for several days or several times a week for several weeks, not limited to some brief moments corresponding to a score of at least 4 on one or more of the following positive and negative symptom scale (PANSS)^[53] symptoms: P1 (delusions), P3 hallucinations), P5 (grandiose thinking), P6 (suspiciousness) and G9 (unusual thought content); 5) This is the first episode of the condition that is being adequately treated. i.e. the patient has not received antipsychotic treatment corresponding to 75% of a defined daily dosage for more than eight weeks (shorter if the symptoms remit); 6) There are no known neurological or endocrine disorders that may have caused the presenting psychotic symptoms; 7) The patient is not mentally retarded with an IQ below 70; 8) Able to understand and speak Norwegian; 9) Able to understand and sign informed consent/assent for minors' document.

Assessments. The primary measure of the incidence study is psychotic caseness as ascertained by SCID (Kiddie SADS for adolescents who are 13–17 years old) assisted by the PANSS interview.

Prodromal Patient Neuroimaging Protocol

A fMRI protocol is set up for the prodromal study providing the possibility to study prodromal patients, and normal controls. The MR imaging is performed with a 1.5 tesla scanner (450 Discovery; GE Medical Systems) equipped with a standard head-and-spine (HNS) coil.

Structural Images. A structural image is acquired after the functional imaging using a BRAVO sequence (GE Healthcare); a T1-weight 3D IR-prepared spoiled gradient echo-sequence with the following parameters: TR/TE/TI = 7.9 ms/3.1 ms/450 ms, FOV = 24 × 19.2 cm. Number of slices is 180 with a thickness of 1 mm. The in-plane sampling matrix is set to 240 × 192 resulting in an iso-tropic resolution of 1 mm. The total scan time is 6 min. 3 s.

Functional Magnetic Resonance Imaging. Working Memory Task. Participants undergoes fMRI scanning while performing a numeric n-back WM task as used in previous studies.^[54–56] The task contains two conditions: (1) in the "2-back" condition, participants are required to press a button when the number they see equales the number seen two numbers before; and (2) in the "0-back" condition, participants have to respond with a button press each time they see the number zero. Numbers between 0 and 9 is displayed for 500 ms with an intertrial interval of 900 ms. Each block consist of 22 stimuli containing three targets and is indicated by an instruction cue displayed for 2 seconds before each block. Stimulation blocks and resting periods alternates within the experiment with a total of six 2-back and six 0-back blocks. During resting periods, volunteers are instructed to fixate on a cross in the center of the screen.

MRI is performed using gradient-echo echo-planar imaging (TR, 2600 ms; TE, 35 ms; flip angle, 90°; matrix, 64 × 64; voxel size, 2 × 4 × 5 mm). The combination of a stimulus onset asynchrony of 1400 ms (500 ms stimulus duration; 900 ms intertrial interval) and a TR of 2600 ms resultes in 13 possible time points of stimulus presentation per TR. Across multiple stimulus presentations, this yields an effective sampling rate of 5 Hz. Twenty-four slices approximately parallel to the bicommissural plane (anterior commissure–posterior commissure plane) are collected, covering the whole brain. Twenty fMRI volumes are acquired per block: 12 during stimulation (2-back or 0-back) and eight during the resting period. Blocks are presented alternately three times in each of the two runs (A B A B A B). A total of 252 volumes are collected.

Resting State Task. Subjects undergoes one 8 min scan during which they performed a resting-state, low-level baseline task (eyes open, visual fixation on a hair-cross-centered in the screen). MRI is performed using gradient-echo echo-planar imaging. The experiment consisted of a single session during which 180 BOLD sensitive EPI volumes are acquired with 25 axial slices (TR, 2500 ms; TE, 40 ms; flip angle, 90°, 5 mm slice thickness, no interslice gap, matrix, 64 × 64; field of view: 240 × 200 mm²; voxel size, 2 × 4 × 5 mm).

Dichotic Listening Task. The paradigm consist of dichotic presentations of pairs of consonant–vowel (CV-) syllables, i.e. two different syllables were simultaneously presented, one to the left and one to the right ear.^[57–59] The syllable pairs is formed combining the six syllables /ba/, /da/, /ga/, /pa/, /ta/, and /ka/ to all possible 30 pairs of unidentical syllables (e.g., /ba/ presented to the left and /da/presented to the right ear), i.e. also including the reversed pairing (e.g., /da/ presented to the left and /ba/ presented to the right ear). The syllables is spoken by an adult Norwegian male voice with constant intensity and intonation. The syllables in each pair are temporally aligned to achieve simultaneous onset of the initial consonants. The stimulus duration varies between 400 and 450 ms. The fMRI paradigm is presented as block-design, including in total nine task blocks (interleaved with a rest block) each containing ten syllable pair presentations, amounting to in total 90 stimulus presentations (equivalent to three times the total set of syllable pairs). The first three blocks are presented with no specific attention instruction (NF), i.e. the subjects are instructed to report the syllable which they heard best in each trial. For the remaining six blocks the subjects are asked to focus their attention to and report the left- (FL) or the right-ear stimulus (FR), respectively. In all three conditions, the instruction is to accurately report the syllable (with no emphasis on response speed). The order of the three FL and the three FR blocks are pseudo-randomised (order: ABBABA). This approach of starting with the NF blocks, followed by the forced attention blocks, is chosen to avoid "carryover" effects that might result from presenting the forced attention conditions first, since individuals might not be able to "not attend" once instructed to attend to a particular side in auditory space.^[60]

Before entering the MR scanner all subjects conducts five practice trials (with the NF instruction) in order to familiarize them with stimulus material and procedure. Here, the subjects are also informed that in addition to the just-practiced NF condition, two other conditions will be presented, during which they will be asked to selectively attend to one ear and only report the syllable presented to this ear. Inside the scanner, instructions are given via head-coil mounted goggles (Nordic Neuro Lab, Bergen, Norway). Each instruction consists of a brief sentence asking the subject to report the syllable which is heard the best (NF), in the right ear (FR), in the left ear (FL), or to relax (rest block). The instruction screen is after 2500 ms replaced by a fixation cross on which the subjects are instructed to focus their eyes. Throughout all blocks, the inter-stimulus interval is 5500 ms. Stimulus administration is controlled by E-Prime software (Psychology Software Tools Inc., Pittsburgh, PA) and the dichotic stimuli is presented using MR-compatible headphones (Nordic Neuro Lab, Bergen, Norway). The subjects' response were given orally and is recorded with an mp3-recorder connected to an MR-compatible microphone.

The resulting recordings will be analyzed and coded. The percentage of correctly reported syllables will be determined separately for the left-ear (LE) and the right-ear (RE) stimuli in each of the three conditions. In order to quantify the effect of attention we will calculate two "attentional gain scores":^[61] (1) the increase in the number of correct right-ear report from NF to FR (defined as: REgain = FR_RE − NF_RE); and (2) the increase of correct left-ear report from NF to FL (LEgain = FL_LE − NF_LE).

Functional imaging is performed using a sparse-sampling echo-planar imaging (EPI) sequence, i.e. EPI volumes are acquired with a repetition time of 5.5 s and an acquisition time of 1.5 s, leaving a silent gap of 4 s, during which the dichotic stimuli are presented and the subjects' verbal response is given.^[62] The experiment consists of a single session during which 180 BOLD sensitive EPI volumes were acquired with 25 axial slices (field of view 240 × 75 mm²; scan matrix 64 × 64; 3 mm slice thickness, no interslice gap; voxel size 1 × 4 × 3 mm, echo time of 35 ms), covering most of the cerebrum. The experimental stimulation follows a block design with nine blocks, three per condition (see above). Each block contains ten volume acquisitions, with one trial per silent gap and lasting for 55 s. Each block of the nine experimental blocks is followed by a rest-block (10 scans, 55 s).

Ethical Approval

The study is approved by the National Committee for Medical and Health Research Ethics (2009/949). Participation in the prodromal study will be based on written informed consent. All data from the Patient Record System for patients registered in the incidence study will be depersonalized by health professionals who already have access to the information before it is delivered to the researchers.