Velligan 2008.

Methods	Randomized controlled trial
Participants	The study location was San Antonio and Austin, Texas, USA 36 patients were randomized to the Cognitive Adaptation Training (PharmCAT), which was focused only on medication and appointment adherence; 37 were randomized to the Cognitive Adaptation Training (Full‐CAT), which focused on many aspects of community adaptation; 32 participants were randomized to the control group The inclusion criteria were: 1) diagnosis of schizophrenia or schizoaffective disorder utilizing the Structured Clinical Interview for Diagnosis, 2) ages of 18 to 60 years, receiving treatment with an oral atypical antipsychotic with the treating physician's recommendation to continue the medication and participate in follow‐up at the Center for Health Care Services, (3) have primary responsibility for taking their own medications, have a stable residence, and 4) able to understand and complete rating scales and neuropsychological testing The exclusion criteria were 1) on clozapine or depot medication, 2) documented history of significant head trauma, seizure disorder, or mental retardation, 3) a history of substance abuse or dependence in the past month, or 4) a history of violence in the past 6 months
Interventions	Intervention: FULL‐CAT Cognitive Adaptation Training (CAT) uses manual‐driven compensatory strategies and supports such as pill containers with alarms, organization of belongings, and activity checklists to prompt and sequence adaptive behaviors in an individual's home environment. CAT strategies are tailored to the specific cognitive impairments and behavioral approaches to goal‐directed activity exhibited by each participant. Environmental supports in Full‐CAT treatment were based upon an assessment of neurocognitive function, behavior, adaptive functioning, and the environment. Interventions for each functional deficit were based on 2 dimensions, (1) level of impairment in executive functions and (2) whether the overt behavior of the individual during performance of goal‐directed activity was characterized more by apathy, disinhibition, or a combination of these styles. According to the CAT model, individuals with poor executive functioning need high levels of structure and more obviously placed environmental cues, while those with somewhat better executive functioning need less structure and more subtle cues. Individuals with apathetic behavior benefit from environmental supports that cue and sequence behavior, those with disinhibition benefit most from the removal of distracting stimuli, and those with mixed behavior benefit from a combination of these strategies. Assessment results yield one of 6 CAT classifications for which interventions can be targeted. Once an individual's CAT classification was determined, strategies for specific functional problems were chosen from the manual. CAT interventions were established, trained, and maintained in the home during weekly visits from a CAT therapist/trainer. Patients in Full‐CAT were seen once weekly for 30 to 45 minutes. The treatment lasted for 9 months and then the patients were followed up for 6 months after the withdrawal of home visits. CAT therapists were individuals with bachelor's or master's degrees in psychology or related fields trained using a combination of didactic and in vivo strategies Intervention: PHARM‐CAT Pharm‐CAT is a subset of the Full‐CAT program, which is a manual‐driven treatment using environmental supports. Patients received assessments of neurocognitive function, behavior, adaptive functioning, and the environment. Interventions in Pharm‐CAT are individualized in the same manner as those in Full‐CAT treatment. However, only interventions that specifically target adherence are used. Additional issues such as transportation were addressed only if they related to taking medication or making it to clinic appointments. Patients in Full‐CAT and Pharm‐CAT were seen once weekly for 30 to 45 minutes. Visits in Pharm‐CAT were necessarily shorter in duration because the focus of treatment was circumscribed around the issue of adherence. Pharm‐CAT is a subset of the Full‐CAT program, which is a manual‐driven treatment using environmental supports. Patients received assessments of neurocognitive function, behavior, adaptive functioning, and the environment. Interventions in Pharm‐CAT were individualized in the same manner as those in Full‐CAT treatment. However, only interventions that specifically targeted adherence were used. Additional issues such as transportation were addressed only if they related to taking medication or making it to clinic appointments. Patients in Full‐CAT and Pharm‐CAT were seen once weekly for 30 to 45 minutes. Visits in Pharm‐CAT were necessarily shorter in duration because the focus of treatment was circumscribed around the issue of adherence. Pharm‐CAT therapists were individuals with bachelor's or master's degrees in psychology or related fields trained using a combination of didactic and in vivo strategies Control: TAU Patients were seen monthly to every 3 months for brief medication visits. They had case managers with high case loads who had little ongoing contact with patients not in crisis
Outcomes	The measures of adherence were per cent adherence from unannounced pill counts conducted in the participants' homes twice during each 3 months in the study. The researcher making the visit requested that he or she be given all pills available to be counted. An adherence per cent was (the number of pills missing from the bottle and assumed taken/number of pills prescribed) x 100. The method required some initial preparation including asking patients to save all empty medication bottles (providing a sign and empty box) and bagging and stapling old bottles of medication so that the researcher would know when pills were taken from multiple bottles. Pill counts could not be blinded due to the obvious nature of environmental supports. Pharmacy records were examined as a secondary measure of adherence that would not be impacted by the obvious nature of environmental supports in the participants' homes. Pharmacy per cent adherence [(number of pills supplied/number days in period) x 100] was calculated. Pharmacy records that overlapped assessment periods were included in the assessment period in which the majority of prescription days fell The patient outcomes were symptomatology, relapse, and functional outcomes. Symptomatology was assessed using an expanded version of BPRS. The psychosis factor score was used to measure positive symptoms; the higher the score, the higher the levels of symptomatology. Relapse was assessed using BPRS. Patients were considered to be relapsed if a score on any of the 4 items increased 2 points to a score of 5 or higher, or if the patient was suicidal, hospitalized, or unable to care for themselves without continual supervision. Functional outcomes were assessed using SOFAS scores conducted during a lengthy semi‐structured interview. Higher scores indicated better adaptive functioning. To further increase validity, collateral information was collected from caregivers and relatives
Notes	―
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Author's note: statistician created randomization tables and informed staff of the randomization after baseline assessments were completed. Staff dealing with patients were not in charge of randomization
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgment of 'Low risk' or 'High risk'. "Participants received a baseline assessment and were then randomized into one of 3 treatment conditions for a period of 9 months" "Randomization was stratified by recruitment site (hospital vs community clinic), gender, and age." (pg 484)
Selective reporting (reporting bias)	Low risk	The study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre‐specified
Other bias	Unclear risk	"These results must be examined within the context of the study's methodological limitations. A significant number of inpatient recruits did not make it to the point of randomization into treatment for this outpatient treatment study. Results can only apply to those individuals treated as outpatients or inpatients who have successfully negotiated the transition from inpatient to outpatient status. Participants in the study had been ill on average for more than a decade. The extent to which these techniques would be helpful to individuals with a more recent onset of schizophrenia should be examined in future research. In future studies including a baseline period of assessment for medication adherence prior to randomization would be important. In‐home pill counts could not be conducted by blinded observers given the nature of environmental supports. However, pharmacy records were not subject to observer bias. It is also likely that more adherent individuals agreed to participate in the study; a common problem in adherence research. Moreover, assessments of medication adherence involve error that may overestimate or underestimate actual adherence. Methodological problems with pill counts and pharmacy records are outlined elsewhere.29 The fact that medication adherence improved, while psychotic symptoms did not suggests that our notions about adequate adherence and optimal dosing may have been formed in the ambiguous environment of partial adherence or negotiation and may need to be altered to maximize the outcomes of our patients. Despite these methodological limitations, the study provides strong support for the benefits of CAT and Pharm‐CAT with respect to improving medication adherence and for the benefits of CAT for improving functional outcomes." (pg 491)
Blinding of outcome assessment (detection bias) Adherence measure	High risk	(PRIMARY) PILL COUNT ‐ "Pill counts could not be blinded due to the obvious nature of environmental supports." As the personnel had to visit the homes of the participants, they had the opportunity to see if the participants were in a certain intervention or control group." (pg 5)
Blinding of outcome assessment (detection bias) Patient outcome	Low risk	(PRIMARY) SYMPTOMATOLOGY ‐ (pg 5) "In an effort to maintain treatment blinds, all subjects and collaterals were asked at the beginning of each assessment neither to divulge information about any visits made by staff of the research project nor to refer to any items they may have received as part of the study. If blinds were broken, alternative raters blind to group assignment completed the remaining assessments."
Blinding of participants (performance bias) Adherence measure	High risk	(PRIMARY) PILL COUNT ‐ Given the method of intervention, it would be easy for the study participants to become unblinded
Blinding of participants (performance bias) Patient outcome	High risk	(PRIMARY) SYMPTOMATOLOGY ‐ This is a subjective measure; there is no information on blinding
Blinding of personnel (performance bias) Adherence measure	Unclear risk	(PRIMARY) PILL COUNT ‐ No information on blinding given. There is insufficient information to permit judgment of 'Low risk' or 'High risk'
Blinding of personnel (performance bias) Patient outcome	Unclear risk	(PRIMARY) SYMPTOMATOLOGY ‐ No information on blinding given. There is insufficient information to permit judgment of 'Low risk' or 'High risk'
Incomplete outcome data (attrition bias) Adherence measure	Unclear risk	(PRIMARY) PILL COUNT ‐ More information is needed about the how many patients from each group had missing information and the reasons for missing information. "For pill count and pharmacy records, respectively, 90 and 83 subjects had available data at baseline and at least one follow‐up." (pg 488)
Incomplete outcome data (attrition bias) Patient outcome	Unclear risk	(PRIMARY) SYMPTOMATOLOGY ‐ Reasons for missing outcome data after randomization are not discussed