. Author manuscript; available in PMC: 2019 Feb 1.

Published in final edited form as: Am J Geriatr Psychiatry. 2017 May 25;26(2):125–133. doi: 10.1016/j.jagp.2017.05.012

Table 2.

Randomized Controlled Trials Assessing Pharmacogenetic Decision Support Tools for Major Depression

Reference	Year	Study design	Sample size	Sponsorship	Sample characteristics	Eligibility	Target genes and report format (if applicable)	Findings
[¹]	2015	12-week prospective double blind RCT. Assay guided prescribing vs treatment as usual Remission rates assessed with baseline and 4 weekly HDRS by independent blinded rater Intolerability events, where patient needed to reduce the dose or stop their antidepressant, were recorded Number of sick days taken off work or studies due to depression were recorded	148	CNSDose, Australia	Guided vs unguided Mean baseline HDRS: 24.81 vs 24.66 (NS) Mean duration of MDE 8.51 vs 8.59 months (NS) Mean number of MDD episodes 2.22 vs 2.18 (NS) Proportion male 42% vs 39% (NS) Mean age (years) 44.2 vs 44.3 (NS) Proportion employed 91% vs 89% (NS)	Inclusion: Age ≥18 years Male and female Primary diagnosis of MDD by DSM-5 criteria assessed by semi-structured psychiatrist interview HDRS score ≥18 Caucasian subjects Exclusion: Other active psychiatric diagnosis Substance use disorder Pregnancy or breastfeeding Hepatic or renal impairment Co-prescription of known CYP2D6, CYP2C19 or ABCB1 inducers/inhibitors Regular grapefruit drinkers Current smoker	Target genes: ABCB1, ABCC1, CYP2C19, CYP2D6 and UGT1A1 Medications: Sertraline, escitalopram, paroxetine, fluoxetine, fluvoxamine, reboxetine, venlafaxine, desvenlafaxine, duloxetine, mirtazapine, agomelantine, clomipramine, nortriptyline, amitriptylline Report format: Pharmacogenetic interpretive report indicated if the patient’s genotype suggested mid-range, high-range or low-range doses were needed.	Outcome 1: Efficacy, by remission (HDRS ≤ 7) Subjects receiving genetically guided prescribing had a 2.52-fold greater chance of remission (95% confidence interval [CI]=1.71–3.73, z=4.66, p<0.0001). The number needed to genotype (NNG)=3 (95% CI=1.7–3.5) to produce an additional remission. Outcome 2: Intolerability events The unguided group were 1.13 times more likely to have medication tolerability problems (95% CI=1.01–1.25, z=2.208, p=0.0272) requiring either dose reduction or cessation. Outcome 3: Sick days The genetically guided group had significantly less risk of taking sick leave (4% versus 15%, p=0.0272) and significantly less duration of sick leave when such was needed (4.3 days versus 7.7 days, p=0.014).
[³]	2013	10-week prospective, double-blind RCT. Assay guided prescribing vs treatment as usual (TAU) Clinicians of patients randomised to the assay guided prescribing arm were provided with the report at first clinic visit (week 2 of study) Study subjects and raters were blinded to the treatment arm for the duration of the study In both arms, antidepressant adjustment started from the first clinic visit (week 2 of study) Assessment data was collected at baseline and 4, 6 and 10 weeks and included the HAMD-17, the FIBSERS, the QIDS-CR and QIDS-SR and the PHQ-9.	51	GeneSight, USA	TAU vs Guided, values as mean ± SD Randomization scheme did not balance for age, gender and ethnicity Mean number of psychiatric medications at baseline 2.7 ± 1.2 vs. 2.9 ± 1.2 (NS) Mean number of previous psychiatric medication trials 4.5 vs 4.3 (NS) Mean age 47.8 ± 13.9 vs 50.6 ± 14.6 (NS) Proportion female 92% vs 69% (p=0.04) Proportion non-Hispanic white 100% vs 96% (NS)	Inclusion: Diagnosis of MDD or DDNOS HAMD-17 score ≥ 14 Exclusion: Other active psychiatric diagnosis Substance use disorder	Target genes: CYP2D6, CYP2C19, CYP1A2, SLC6A4, HTR2A. Medications: SSRIs: citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine and sertraline; SNRIs: desvenlafaxine, duloxetine and venlafaxine; TCAs: amitriptyline, clomipramine, desipramine, doxepin, imipramine and nortriptyline; MAOi: selegiline; Atypical antidepressants: bupropion, trazodone and mirtazapine; Typical antipsychotics: chlorpromazine, fluphenazine, haloperidol, perphenazine, thioridazine and thiothixene; Atypical antipsychotics: aripiprazole, clozapine, iloperidone, olanzapine, quetiapine, risperione and ziprasidone. Report format: The interpretive report categorized each of the 26 psychotropic medications into either a green (‘use as directed’), yellow (‘use with caution’) or red category (‘use with increased caution and with more frequent monitoring’) phenotype.	Outcome 1: Utilisation of GeneSight The likelihood of clinicians switching, augmenting or dose-adjusting medication regimens during the trial period was the same in both groups (Genesight=53% vs TAU=58%; X²=0.19; p=0.66) All GeneSight subjects on a red bin medication were changed over during the study period, by comparison 50% of TAU subjects were switched or dose adjusted (X²=5.09; p=0.02) No difference in the mean number of psychotropics prescribed between groups at the end of the study period (Genesight=1.9 vs TAU=1.7; p=0.27) No difference in the number of mental health visits between groups at the end of the study (X²=6.86; df=11; p=0.81) Outcome 2: Efficacy Greater than double the likelihood of response (GeneSight=36%; TAU=20.8%; OR=2.14; 95% CI 0.59–7.69) and remission (GeneSight=20%; TAU=8.3%; OR=2.75; 95% CI 0.48–15.80) in the GeneSight group measured by HAMD-17 at week 10. Mean percent improvement in depressive symptoms on HAMD-17 was higher for the GeneSight group over treatment as usual (30.8% vs 20.7%; p=0.28) Not statistically significant improvement in PHQ-9 (Genesight=35.4% vs TAU=21.3%; F=1.84; p=0.18) or QIDSC-16 scores (Genesight=27.6% vs TAU=22.1%)
[⁷]	2016	3-month prospective, naturalist, double-blind RCT Assay guided prescribing vs treatment as usual Evaluated at baseline, 6 and 12 weeks and with telephone interviews at 4, 8, and 12 weeks by PGI-I, 17-HDRS, FIBSERS, SDI, SATMED-Q.	316	Neuropharmagen, Spain	Sample Characteristics not clear from abstract but authors have noted: The study cohort displayed a large diversity in terms of duration of disease, number of previous treatments, depression severity and psychiatric comorbidities.	Inclusion and Exclusion criteria Inclusion: Adult patients Diagnosis of MDD	Target Genes, medications and report format are not specified in the abstract.	Outcome 1: Efficacy Participants in the guided group showed a higher reduction in HDRS at 6 weeks (p=0.0364), but not at 12 weeks. Patients with baseline HDRS ≥14 (n=254), and in those who had received 1 to 3 previous treatments (n=190) had significant reductions in PGI-I at 12 weeks and HDRS at 6 and 12 weeks. A higher proportion of responders (PGI-I ≤2) was observed at 12 weeks in the guided group (47.8% vs 36.1%, p = 0.0476, OR = 1.62 [95% CI 1.00–2.61]). No statistical significance in the rate of sustained response was observed at week 4 or 8. Outcome 2: Tolerance Of the participants reporting side-effects at baseline via FIBSER score, the likelihood of reaching a score <3 was higher among guided participants at 6 weeks (66.7% vs 50.0%, p = 0.0294, OR 2.00 [95% CI: 1.07–3.75]), and was maintained at 12 weeks (68.5% vs. 51.4%, p = 0.0260, 2.06 [95% CI: 1.09 – 3.89]).

Reference

Year

Study design

Sample size

Sponsorship

Sample characteristics

Eligibility

Target genes and report format (if
applicable)

Findings

[¹]

2015

12-week prospective double blind RCT. Assay guided prescribing vs treatment as usual
Remission rates assessed with baseline and 4 weekly HDRS by independent blinded rater
Intolerability events, where patient needed to reduce the dose or stop their antidepressant, were recorded
Number of sick days taken off work or studies due to depression were recorded

148

CNSDose, Australia

Guided vs unguided

Mean baseline HDRS: 24.81 vs 24.66 (NS)
Mean duration of MDE 8.51 vs 8.59 months (NS)
Mean number of MDD episodes 2.22 vs 2.18 (NS)
Proportion male 42% vs 39% (NS)
Mean age (years) 44.2 vs 44.3 (NS)
Proportion employed 91% vs 89% (NS)

Inclusion:

Age ≥18 years
Male and female
Primary diagnosis of MDD by DSM-5 criteria assessed by semi-structured psychiatrist interview
HDRS score ≥18
Caucasian subjects

Exclusion:

Other active psychiatric diagnosis
Substance use disorder
Pregnancy or breastfeeding
Hepatic or renal impairment
Co-prescription of known CYP2D6, CYP2C19 or ABCB1 inducers/inhibitors
Regular grapefruit drinkers
Current smoker

Target genes:
ABCB1, ABCC1, CYP2C19, CYP2D6 and UGT1A1

Medications:
Sertraline, escitalopram, paroxetine, fluoxetine, fluvoxamine, reboxetine, venlafaxine, desvenlafaxine, duloxetine, mirtazapine, agomelantine, clomipramine, nortriptyline, amitriptylline

Report format:
Pharmacogenetic interpretive report indicated if the patient’s genotype suggested mid-range, high-range or low-range doses were needed.

Outcome 1: Efficacy, by remission (HDRS ≤ 7)

Subjects receiving genetically guided prescribing had a 2.52-fold greater chance of remission (95% confidence interval [CI]=1.71–3.73, z=4.66, p<0.0001).
The number needed to genotype (NNG)=3 (95% CI=1.7–3.5) to produce an additional remission.

Outcome 2: Intolerability events

The unguided group were 1.13 times more likely to have medication tolerability problems (95% CI=1.01–1.25, z=2.208, p=0.0272) requiring either dose reduction or cessation.

Outcome 3: Sick days

The genetically guided group had significantly less risk of taking sick leave (4% versus 15%, p=0.0272) and significantly less duration of sick leave when such was needed (4.3 days versus 7.7 days, p=0.014).

[³]

2013

10-week prospective, double-blind RCT. Assay guided prescribing vs treatment as usual (TAU)
Clinicians of patients randomised to the assay guided prescribing arm were provided with the report at first clinic visit (week 2 of study)
Study subjects and raters were blinded to the treatment arm for the duration of the study
In both arms, antidepressant adjustment started from the first clinic visit (week 2 of study)
Assessment data was collected at baseline and 4, 6 and 10 weeks and included the HAMD-17, the FIBSERS, the QIDS-CR and QIDS-SR and the PHQ-9.

GeneSight, USA

TAU vs Guided, values as mean ± SD

Randomization scheme did not balance for age, gender and ethnicity
Mean number of psychiatric medications at baseline 2.7 ± 1.2 vs. 2.9 ± 1.2 (NS)
Mean number of previous psychiatric medication trials 4.5 vs 4.3 (NS)
Mean age 47.8 ± 13.9 vs 50.6 ± 14.6 (NS)
Proportion female 92% vs 69% (p=0.04)
Proportion non-Hispanic white 100% vs 96% (NS)

Inclusion:

Diagnosis of MDD or DDNOS
HAMD-17 score ≥ 14

Exclusion:

Other active psychiatric diagnosis
Substance use disorder

Target genes:
CYP2D6, CYP2C19, CYP1A2, SLC6A4, HTR2A.

Medications:
SSRIs: citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine and sertraline;
SNRIs: desvenlafaxine, duloxetine and venlafaxine;
TCAs: amitriptyline, clomipramine, desipramine, doxepin, imipramine and nortriptyline;
MAOi: selegiline;
Atypical antidepressants: bupropion, trazodone and mirtazapine;
Typical antipsychotics: chlorpromazine, fluphenazine, haloperidol, perphenazine, thioridazine and thiothixene;
Atypical antipsychotics: aripiprazole, clozapine, iloperidone, olanzapine, quetiapine, risperione and ziprasidone.

Report format:
The interpretive report categorized each of the 26 psychotropic medications into either a green (‘use as directed’), yellow (‘use with caution’) or red category (‘use with increased caution and with more frequent monitoring’) phenotype.

Outcome 1: Utilisation of GeneSight

The likelihood of clinicians switching, augmenting or dose-adjusting medication regimens during the trial period was the same in both groups (Genesight=53% vs TAU=58%; X²=0.19; p=0.66)
All GeneSight subjects on a red bin medication were changed over during the study period, by comparison 50% of TAU subjects were switched or dose adjusted (X²=5.09; p=0.02)
No difference in the mean number of psychotropics prescribed between groups at the end of the study period (Genesight=1.9 vs TAU=1.7; p=0.27)
No difference in the number of mental health visits between groups at the end of the study (X²=6.86; df=11; p=0.81)

Outcome 2: Efficacy

Greater than double the likelihood of response (GeneSight=36%; TAU=20.8%; OR=2.14; 95% CI 0.59–7.69) and remission (GeneSight=20%; TAU=8.3%; OR=2.75; 95% CI 0.48–15.80) in the GeneSight group measured by HAMD-17 at week 10.
Mean percent improvement in depressive symptoms on HAMD-17 was higher for the GeneSight group over treatment as usual (30.8% vs 20.7%; p=0.28)
Not statistically significant improvement in PHQ-9 (Genesight=35.4% vs TAU=21.3%; F=1.84; p=0.18) or QIDSC-16 scores (Genesight=27.6% vs TAU=22.1%)

[⁷]

2016

3-month prospective, naturalist, double-blind RCT
Assay guided prescribing vs treatment as usual
Evaluated at baseline, 6 and 12 weeks and with telephone interviews at 4, 8, and 12 weeks by PGI-I, 17-HDRS, FIBSERS, SDI, SATMED-Q.

316

Neuropharmagen, Spain

Sample Characteristics not clear from abstract but authors have noted:

The study cohort displayed a large diversity in terms of duration of disease, number of previous treatments, depression severity and psychiatric comorbidities.

Inclusion and Exclusion criteria

Inclusion:

Adult patients Diagnosis of MDD

Target Genes, medications and report format are not specified in the abstract.

Outcome 1: Efficacy

Participants in the guided group showed a higher reduction in HDRS at 6 weeks (p=0.0364), but not at 12 weeks.
Patients with baseline HDRS ≥14 (n=254), and in those who had received 1 to 3 previous treatments (n=190) had significant reductions in PGI-I at 12 weeks and HDRS at 6 and 12 weeks.
A higher proportion of responders (PGI-I ≤2) was observed at 12 weeks in the guided group (47.8% vs 36.1%, p = 0.0476, OR = 1.62 [95% CI 1.00–2.61]). No statistical significance in the rate of sustained response was observed at week 4 or 8.

Outcome 2: Tolerance

Of the participants reporting side-effects at baseline via FIBSER score, the likelihood of reaching a score <3 was higher among guided participants at 6 weeks (66.7% vs 50.0%, p = 0.0294, OR 2.00 [95% CI: 1.07–3.75]), and was maintained at 12 weeks (68.5% vs. 51.4%, p = 0.0260, 2.06 [95% CI: 1.09 – 3.89]).

Abbreviations:

CPGx Combinatorial pharmacogenomic test, trade name of Assurex Health Inc.

CGI-S Clinical Global Impressions – Severity of Illness

CGI-I Clinical Global Impressions – Improvement

DDNOS Depressive disorder not otherwise specified

DSM Diagnostic and Statistical Manual of Mental Disorders

FIBSERS Frequency, Intensity, and Burden of Side Effects Rating Scale

HAMD-17 17-item Hamilton Rating Scale for Depression

HDRS 17-item Hamilton Depression Rating Scale

ICD International Statistical Classification of Diseases and Related Health Problems

MDD Major Depressive Disorder

NS Not statistically significant (p>0.05)

PDC Proportion of days covered

PGI-I Patient Global Impression of Improvement scale

PHQ-9 9-item Patient Health Questionnaire

QIDS-C16 16-item Quick Inventory of Depression Symptomatology Scales – Clinician Rated

QIDS-CR 16-item Quick Inventory of Depression Symptomatology Scales – Clinician Rated

QIDS-SR 16-item Quick Inventory of Depression Symptomatology Scales – Subject Rated

Q-LES-Q-SF Quality of Life Enjoyment and Satisfaction Questionnaire Short Form

SAS Zung Self-Rated Anxiety Scale

SATMED-Q Treatment Satisfaction with Medicines Questionnaire

SD Standard deviation

SDI Sheehan Disability Inventory

TAU Treatment as usual

UKU Udvalg for Kliniske Undersogelser Side Effect Rating Scale

Table References:

Singh, A.B., Improved Antidepressant Remission in Major Depression via a Pharmacokinetic Pathway Polygene Pharmacogenetic Report. Clin Psychopharmacol Neurosci, 2015. 13(2): p. 150–6.

Winner, J.G., et al., A prospective, randomized, double-blind study assessing the clinical impact of integrated pharmacogenomic testing for major depressive disorder. Discov Med, 2013. 16(89): p. 219–27.

⁷

Pérez, V., et al. Effectiveness of pharmacogenetic information in the treatment of major depressive disorder: results from the AB-GEN randomized clinical trial. in 29th ECNP Congress. 2016. Vienna.