Table 1.
Characteristics of randomized controlled trials for young people with treatment-resistant depression
| Study | Setting for recruitment | Setting for intervention | Definition treatment resistance | Inclusion and exclusion criteria (psychiatric disorders) | n | Age/ Gender | Duration of illness/Duration of this episode (in each group) | Comorbidity/ Severity of illness/Suicide risk | Intervention/Length | Comparison | Follow-up |
|---|---|---|---|---|---|---|---|---|---|---|---|
| ADAPT47 | Routine outpatient clinical services in Manchester and Cambridge, UK; for the first year, four cases recruited from an adolescent inpatient unit | Participants were treated in routine outpatient CAMHS settings by the trial psychiatrists | “Persistent major depression”55 “nonremitting depression” defined as nonresponse to 2 brief initial sessions including support and educational interventions with psychiatrist. In addition, 34 adolescents with proven nonremitting depression (failed trial of psychosocial intervention before referral) were included. Note 22 cases were deemed severe enough; and another 29 were already on an SSRI (the majority also having had previous psychosocial intervention) and these cases all bypassed the brief initial intervention and enter the trial directly. “Most participants had already been treated and would have received psychosocial interventions before medication” page 4 2007 BJP publication47 | Inclusion criteria: age 11–17 years and ≥4 DSM-IV depressive symptoms (including one core mood symptom of sadness, irritability, or anhedonia) during 2-week period and present on assessment plus HoNOSCA score ≥7 Exclusion criteria: schizophrenia or bipolar disorder; need for immediate inpatient admission; previous optimal treatment with both SSRI and CBT with no effect |
208 | Mean: 14 years (SD 1.5) Female: 74% |
Total median (range) index episode: 40 weeks (3–624) Fluoxetine: 52 (4–624) fluoxetine + CBT 32 (3–260) |
92% had major depressive disorder; 8% had minor depression. Mean number of symptoms: fluoxetine + CBT 6.6 (SD 1.5); fluoxetine 6.4 (SD 1.4). CDRS-R t-scores were: total 75.0 (7.4); fluoxetine 75.3 (6.7); fluoxetine + CBT 75.1 (6.7) CDRS-R raw scores: total 58.8 (10.4); fluoxetine 59.0 (9.5); fluoxetine + CBT 58.9 (10.5) 88.5% were currently comorbid for at least one other psychiatric disorder, majority of which were anxiety disorders. Suicidality: fluoxetine, ideation 42.7%, attempts 20.4%; fluoxetine + CBT, ideation 38.1%, attempts 12.4% |
Weekly CBT for 12 weeks with fortnightly sessions for an additional 12 weeks in addition to and SSRI and routine clinical care. Routine care consisted of standard interventions given to any depressed adolescent in NHS clinics: regular monitoring of mental state; psychoeducation; reflection, support and encouragement to adolescents and their families; problem solving; attention to co-morbidity; and liaison with other professionals, such as teachers and social workers | SSRI (primarily fluoxetine, unless participant already prescribed another SSRI) alone for 28 weeks in addition to routine clinical care. Fluoxetine dosage: 10 to 20 mg/day to a maximum of 60 mg/day from 6 weeks. Participants seen regularly for prescription and monitoring by study psychiatrists. Routine care consisted of standard interventions given to any depressed adolescent in NHS clinics: regular monitoring of mental state; psychoeducation; reflection, support and encouragement to adolescents and their families; problem solving; attention to co-morbidity; and liaison with other professionals, such as teachers and social workers | 28 weeks (from baseline) |
| Birmaher46 | Mayview State Hospital inpatients | Inpatients | Referred for long-term hospitalization due to failing to respond to several psychosocial and/or pharmacological inpatient interventions at university or community hospitals | Inclusion criteria: Age: 12–18 Diagnosis: nonpsychotic major depressive disorder (DSM-II-R) for at least 3 months and HDRS score ≥ 15 Exclusion criteria: lifetime presence of psychotic disorder, eating disorder, bipolar I or II disorder, substance abuse within last 6 months |
27 | Mean: 16.2 (SD 1.4) Female: 70% |
Total mean index episode 61.2 weeks (SD 31.4) median 52 weeks; AMI mean index episode 65.69 weeks (SD 26.73); placebo mean index episode 57.07 weeks (SD 35.80) |
Mean HDRS was 22.4 (SD 7.3) 6 participants in AMI group considered suicidal; 5 participants in placebo group considered suicidal Total comorbidity unclear, however, table 1 shows at least a quarter of participants had some comorbidity | Amitriptyline for 10 weeks Dosage: daily dosage increased by 50 mg/week to a maximum of 5 mg/kg/day or 300 mg/day or amitriptyline plus NTP plasma levels no greater than 300 ng/mL. Dosage was not increased if patient showed improvement. During the protocol patients were allowed to take lorazepam for severe agitation or insomnia. They also participated in psychosocial interventions (eg, groups, placement preparation). | Placebo for 10 weeks | None reported |
| Robins45 | Primary care | Psychiatric outpatients | Nonresponders to 8 weeks of fluoxetine, on at least 40 mg/day | Inclusion criteria: age 13–17 years; diagnosis of major depressive episode (DSM-IV criteria) from major depressive disorder or bipolar disorder. Exclusion criteria: suicide risk defined as medically |
NA | NA | NA | NA | Fluoxetine augmented by lamotrigine for 8 weeks | Sertraline for 8 weeks | NA |
| TORDIA48 | Clinical sources (79.9%) and advertisements (20.1%) | Multiplesite study in outpatient clinics | Failure to respond to SSRI treatment regimen of at least 8 weeks, the last 4 of which were at a dosage of at least 40 mg/day fluoxetine (or equivalent). Also included participants, who after attempting a dosage comparable to 40 mg/day fluoxetine could only tolerate a dose that was equivalent to 20 mg/ day fluoxetine for at least 4 weeks (19/334). Note exclusion of participants with ≥ 2 failed trials of SSRIs or history of nonresponse to venlafaxine or to CBT (≥ 7 sessions) |
Inclusion criteria: age 12–18 years; diagnosis: depressive disorder (DSM-IV ) plus CDRS-R score ≥ 40 and CGI-S score ≥ 4. Exclusion criteria: bipolar spectrum disorders; psychoses; pervasive developmental disorders or autism; eating disorders; substance abuse of dependence |
334 | Mean 16 years, female 70% | Total duration of current episode (median 17 months SSRI groups (mean): 23.5 (SD 21.6) Venlafaxine groups (mean): 21.4 (SD 19.0) CBT groups (mean): 22.6 (SD 21.4) Non- CBT groups (mean): 22.3 (SD 19.4) |
Total: moderately severe depression CDRS-R = 59 SSRI groups (mean CDRS-R): 59.9 (SD 10.6) Venlafaxine groups (mean CDRS-R): 57.8 (SD 10.1) CBT groups (mean CDRS-R): 58.4 (SD 9.7) Non-CBT groups (mean CDRS-R): 59.2 (SD 11.0) 72.1% first episode 58.5% clinically significant suicidal ideation 51.5% had at least one comorbid disorder, the majority of which were anxiety disorders or dysthymia |
SSRI alone or venlafaxine alone for 12 weeks. Dosage: For SSRI 10 mg/ day for week 1 and 20 mg/day for weeks 2 to 6 with option to increase to maximum of 60 mg/ day thereafter. For venlafaxine dosages for weeks 1 to 4 were 7.5, 75, 112.5, and 150 mg with option to increase to 225 mg at week 6. Pharmacotherapy sessions were between 30 and 60 minutes; conducted by psychiatrists or master’s degree level nurses supervised by psychiatrist; consisted of safety assessment and occurred weekly for 4 weeks and biweekly thereafter. All participants received family psychoeducation at intake, 6-week midpoint and 12- week end of acute treatment | Addition of CBT to SSRI or venlafaxine. CBT included 12 weekly sessions of CBT of 60 to 90 minute duration, 3 to 6 of which were to be family sessions. Therapists were at least master’s level with experience in CBT. CBT drew on manuals that emphasize cognitive restructuring and behavioral activation, emotion regulation, social skills and problem solving; and that also emphasize parent-child sessions to decrease criticism and improve support, family communication and problem solving. Modules were flexibly applied depending on clinical need |
24 weeks |
Abbreviations: CBT, cognitive behavioral therapy; SSRIs, selective serotonin reuptake inhibitors; SD, standard deviation; CGI, Clinical Global Impression; CDRS-R, Children’s Depression Rating Scale-Revised; HoNOSCA, Health of the Nation Outcome Scales for Children and Adolescents; DSM, Diagnostic and Statistical Manual of Mental Disorders; CAMHS, Child and Adolescent Mental Health Service; NHS, National Health Service.