Table 1.
Overview of the effect of pharmacological agents on the fronto-cingulo-parietal cognitive control network.
| Reference | Diagnosis | N (treated) | N (PLC arm) | N (CTRL arm) | Study design | Treatment | Duration | Task | Main behavioral results | Main fMRI results | Timepoint and/or group comparisons | Task contrast |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Acetylcholinesterase inhibitors | ||||||||||||
| Nahas et al. (58) | SCZ (atypical antipsychotics) | 6 | – | – | Randomized double-blind PLC-controlled crossover design | Donepezil adjunctive treatment | 12 weeks | Covert verbal fluency task | No changes in task performance over time | On donepezil relative to PLC,  left IFG and left insula activity |
Patients (donepezil vs. PLC) | Word generation vs. rest |
| Aasen et al. (59)A | SCZ (antipsychotics) | 11 | 9 | – | Randomized double-blind PLC-controlled trial | Rivastigmine adjunctive treatment | 12 weeks | Number detection task | No (between-group) differences in task performance (over time) | – | – | – |
| Kumari et al. (60)A | SCZ (atypical antipsychotics) | 11 | 10 | – | Randomized double-blind PLC-controlled trial | Rivastigmine adjunctive treatment | 12 weeks | n-back | No (between-group) differences in task performance (over time) | Over time and relative to PLC patients at T1, no in right SFG activity |
Rivastigmine (T0, T1) vs. PLC (T0, T1) | 1-back vs. rest |
| Anticonvulsants | ||||||||||||
| Pavuluri et al. (61) | BD (pediatric; mania or mixed) | 13 | – | 13; T0, T1 | Open-label trial | Typical antipsychotics (weeks 1–4); lamotrigine (weeks 1–14) | 14 weeks | Go/no go | Overall relative to CTRL,  accuracy on No Go trials |
Over time and relative to CTRL, greater in left PFC and right MFG activity |
Lamotrigine (T0–T1) vs. CTRL (T0–T1) | Go vs. No Go |
| Over time and similar to CTRL, accuracy on Go trials |
At T1 relative to CTRL, left M1* activity |
Lamotrigine (T1) vs. CTRL (T0) | Go vs. No Go | |||||||||
| Pavuluri et al. (62)C | BD (pediatric; mania or mixed) | 11 | – | 14; T0, T1 | Randomized double-blind trial | Divalproex | 6 weeks | Go/no go | At T0 relative to CTRL, discrimination sensitivity; comparable to CTRL at T1E
|
Over time relative to CTRL, greater in left subgenual ACC and left insula FC in affective network |
Divalproex (T0–T1) vs. CTRL (T0–T1) | During response inhibition |
| Schneider et al. (63) | BD (pediatric; mania or mixed) | 10 | – | 9; T0 | Open-label trial | Carbamazepine | 8 weeks | CPT – identical pairs | At T0 and T1 relative to CTRL at T0, accuracy |
Over time, anterior PFC activity; n.s. at T1 relative to CTRL at T0 |
Carbamazepine (T0–T1); carbamazepine (T1) vs. CTRL (T0) | 1-back vs. “1” detection |
| Antidepressants: selective serotonin reuptake inhibitors and serotonin–noradrenaline reuptake inhibitors | ||||||||||||
| Walsh et al. (64) | Major depression | 20 | – | 20; T0–T2 | Open-label trial | Fluoxetine | 8 weeks | n-back | Over time relative to CTRL, 3-back accuracy; At T0–T2 relative to CTRL, reaction times |
– | – | – |
| Aizenstein et al. (65) | Late-life depression | 13 | – | 13; T0 | Open-label trial | Paroxetine | 12 weeks | Spatial incompatibility task | At T1 relative to CTRL at T0, accuracy |
Over time, right DLPFC activity; at T1 relative to CTRL at T0, left DLPFC activity |
Paroxetine (T0 vs. T1); paroxetine (T1) vs. CTRL (T0) | Contralateral vs. baseline, ipsilateral vs. baseline |
| Wagner et al. (66)D | Major depression | 12 | – | 20; T0 | Open-label trial | Citalopram | 6 weeks | Stroop color-word task | Over time, greater in reaction time for incongruent trials, relative to congruent trialsF
|
Over time, right VLPFC, SMA, IPL, and SPL activity |
Citalopram (T0 vs. T1); citalopram (T0, T1) vs. reboxetine (T0, T1) | During incongruent condition |
| At T1 relative to CTRL at T0, n.s. group differencesF | Patients (T1) vs. CTRL (T0) | During incongruent condition | ||||||||||
| Gyurak et al. (67) | Major depression | 79 | – | 34; T0, T1 | Randomized open-label trial | Escitalopram (n = 26), Sertraline (n = 27), Venlafaxine ER (n = 26) | 8 weeks | Go/No Go | – | Over time, remitters and CTRL show DLPFC activity; over time, no change in hypo-DLPFC activity of non-remitters |
CTRL (T0 vs. T1); remitted (T0, T1) vs. non-remitted (T0, T1) | Go vs. No Go |
| At T0 and T1, n.s. group differences in IPL activity between SSRI remitters and CTRL | Remitted (T0/T1) vs. CTRL (T0/T1) | Go vs. No Go | ||||||||||
| At T0, IPL activity in SNRI remitters than CTRL and SSRI remitters |
Treatment (SSSRI, SNRI) vs. status (remitted, non-remitted, CTRL) vs. time (T0, T1) | Go vs. No Go | ||||||||||
| At T1, IPL activity in SNRI remitters than in CTRL | ||||||||||||
| van der Wee et al. (68) | OCD | 14 | – | – | Randomized double-blind trial | Paroxetine (n = 9), venlafaxine (n = 5) | 12 weeks | n-back | Over time, responders, but not non-responders, accuracy |
Over time and relative to non-responders, mean fronto-cingulo-parietalG activity |
Remitted (T0, T1) vs. non-remitted (T0, T1) | 2-back vs. 0-back, 1-back vs. 0-back |
| Han et al. (69) | OCD | 10 | – | 20; T0 | Open-label trial | Escitalopram (n = 9), fluoxetine (n = 1) | 16 weeks | Task-switching paradigm | At T0 and T1 relative to CTRL, accuracy. Over time, task-switching costs (RT) |
Over time, right ACC, right insula, right PCG, and right PC activity |
Patients (T0 vs. T1) | Task switching vs. task-repeat |
| At T1 relative to CTRL at T0, DLPFC†, DMPFC†, right MFC† and PC† activity, and left insula* activity |
Patients (T1) vs. CTRL (T0) | Task switching vs. task-repeat | ||||||||||
| Atypical antipsychotics | ||||||||||||
| Pavuluri et al. (62)C | BD (pediatric; mania or mixed) | 11 | – | 14; T0 and T1 | Randomized double-blind trial | Risperidone | 6 weeks | Go/no go | At T0 relative to CTRL, discrimination sensitivity; comparable to CTRL at T1E
|
Over time relative to CTRL, greater in insular FC in affective network |
Risperidone (T0–T1) vs. CTRL (T0–T1) | During response inhibition |
| Schneider et al. (63) | BD (pediatric; mania or mixed) | 10 | 7 | 10; T0 | Randomized double-blind PLC-controlled trial | Ziprasidone | 4 weeks | CPT – identical pairs | No between-group differences in task performance (over time) | Over time relative to PLC patients, greater in right VLPFC/OFC activity |
Ziprasidone (T0–T2) vs. PLC (T0–T2) | 1-back vs. “1” detection |
| At T1 and T2 compared to CTRL at T0, n.s. group differences in VLPFC/OFC activity | Patients (T0/T1/T2) vs. CTRL (T0) | 1-back vs. “1” detection | ||||||||||
| Snitz et al. (70) | FEP | 11 | – | 16; T0 and T1 | Open-label trial | Risperidone (n = 7); olanzapine (n = 3); quetiapine (n = 1) | 4 weeks | Spatial incompatibility task | At T0 and T1 relative to CTRL, reaction times |
Over time, ACC, but not DLPFC, activity |
Patients (T0 vs. T1) | Contralateral vs. baseline, ipsilateral vs. baseline |
| At T1 relative to CTRL, n.s. group differences in DLPFC and ACC activity | Patients (T1) vs. CTRL (T1) | Contralateral vs. baseline, ipsilateral vs. baseline | ||||||||||
| Meisenzahl et al. (71) | SCZ | 12 | – | 12; T0 | Open-label trial | Quetiapine | 12 weeks | n-back (degraded and non-degraded) | No (between-group) differences in task performance (over time) | Over time, left VLPFC (non-degraded) and right precuneus (degraded) activity |
Quetiapine (T0 vs. T1) | 2-back vs. 0-back |
| Keedy et al. (72) | FEP | 9 | – | 9; T0 and T1 | Open-label trial | Risperidone (n = 6), ziprasidone (n = 1), haloperidol (n = 2) | 4–6 weeks | Visual attention task | – | Over time, left FEF activity and IPS and VMPFC activity; n.s. at T1 relative to CTRL |
Patients (T0 vs. T1); Patients (T1) vs. CTRL (T1) | Prosaccade vs. fixation |
| At T1 relative to CTRL, supramarginal gyri*, insula*, DLPFC*, SEF† and ACC activity |
Patients (T0 vs. T1); Patients (T1) vs. CTRL (T1) | Prosaccade vs. fixation | ||||||||||
| Ikuta et al. (74) | FEP | 14 | – | 14; T0 and T1 | Randomized double-blind trial | Risperidone or aripiprazole (n not specified) | 12 weeks | Multi-source inference task | Over time, response accuracy; at T1 relative to CTRL, accuracy |
Over time, SFG activity; left SFG and rostral PFC activity |
Patients (T0 vs. T1) | Interference vs. control |
| Keedy et al. (73) | FEP | 14 | – | 12; T0 and T1 | Open-label trial | Risperidone (n = 12), aripiprazole (n = 2) | 4–6 weeks | Visual attention task | No (between-group) differences in prosaccade task performance (over time) | Over time, SEF, IPS and SPC activity; at T1 relative to CTRL, n.s. group differences |
Patients (T0 vs. T1); Patients (T1) vs. CTRL (T1) | Prosaccade vs. fixation |
| Over time, anticipatory saccades during predictive saccade task; at T1 relative to CTRL, n.s. differences |
Over time, left IPS activity and DLPFC activity; n.s. group differences |
Patients (T0 vs. T1); Patients (T1) vs. CTRL (T1) | Predictive saccade vs. fixation | |||||||||
| Benzodiazepines | ||||||||||||
| Wilcox et al. (75) | Alcohol use disorder; comorbid anxiety | 7 | – | 9; T0 | Open-label trial | Lorazepam plus disulfiram | 5–7 days | Multimodal stroop task | Overall relative to CTRL at T0, reaction times |
Over time, right IPL and insula deactivity |
Lorazepam + disulfiram (T0 vs. T1) | Incongruent vs. congruent (Scan 1), incongruent + congruent (Scan 2) |
| COMT inhibitors | ||||||||||||
| Ashare et al. (76) | Smoking dependence (24-h abstinent) | 20 | – | – | Randomized double-blind PLC-controlled crossover design | Tolcapone | 8 days | n-back | On tolcapone relative to PLC, accuracy |
On tolcapone relative to PLC, VMPFC deactivity |
Patients (tolcapone vs. PLC) | 0 + 1 + 2 + 3 back vs. baseline |
| On tolcapone relative to PLC, reaction times for Val/Val, reaction times for Val/Met |
On tolcapone relative to PLC, MFG activity and VMPFC deactivity in Val/Val and MFG and right DLPFC activity in Val/Met |
Patients (tolcapone, PLC) for genotype (Val/Val, Val/Met) | 0 + 1 + 2 + 3 back vs. baseline | |||||||||
| Grant et al. (77) | Pathological gambling | 12 | – | 12; T0 | Open-label trial | Tolcapone | 8 weeks | Tower of London task | No overall between-group differences in task performance | Over time, fronto-cingulo-parietalH activity; at T1, fronto-cingulo-parietalH activity normalized to CTRL at T0 |
Tolcapone (T0 vs. T1); tolcapone (T1) vs. CTRL (T0) | Planning condition vs. counting condition |
| Nicotinic receptor agonists | ||||||||||||
| Tregellas et al. (79)B | SCZ (non-smoking; antipsychotics) | 16 | – | – | Randomized double-blind PLC-controlled crossover design | Varenicline | 4 weeks | Visual attention task | – | – | – | – |
| Tregellas et al. (80)B | SCZ (non-smoking; antipsychotics) | 16 | – | – | Randomized double-blind PLC-controlled crossover design | DMXB-A | 4 weeks | Visual attention task | – | On DMXB-A 150 and 75 mg relative to PLC, IPL and MFG DMN activity and precuneus DMN activity |
Patients (150 mg vs. PLC; 75 mg vs. PLC) | During prosaccade and rest |
| Loughead et al. (78) | Smoking dependence (72-h abstinent) | 22 | – | – | Randomized double-blind PLC-controlled crossover design | DMXB-A | 13 days | n-back | On varenicline relative to PLC, reaction times in highly dependent smokers, but not lowly dependent smokers |
On varenicline relative to PLC, ACC and DLPFC activity; PFC activity (peak in right SFG and left IFG) |
Patients (varencline vs. PLC) | 3-back vs. 0-back, 2-back vs. 0-back, 1-back vs. 0-back |
| Norepinephrine reuptake inhibitors | ||||||||||||
| Schulz et al. (81) | ADHD (pediatric) | 16 | – | – | Randomized double-blind trial | Atomoxetine; MPH comparison (n = 18) | 6–8 weeks | Go/No Go | Over time and similar to MPH, accuracy on No Go trials |
Over time and similar to MPH, M1 activity |
Atomoxetine (T0–T1) vs. methylphenidate (T0–T1) | Go vs. No Go |
| Over time and similar to MPH, reaction time and reaction time variability on Go trials |
Over time and relative to MPH, right IFG, left ACC, left SMA, and PCG activity (MPH activity in these regions) |
Atomoxetine (T0–T1) vs. methylphenidate (T0–T1) | Go vs. No Go | |||||||||
| Bush et al. (82) | ADHD (adults) | 11 | 10 | – | Randomized trial | Atomoxetine; MPH comparison (n = 11) | 6 weeks | Multi-source interference task | No differences in task performance (over time) | Over time, right DLPFC, left IPL, left SMA, and left insula activity |
Atomoxetine (T0 vs. T1) | Interference vs. control |
| Chou et al. (83) | ADHD (pediatric) | 22 | – | 20; T0 | Randomized trial | Atomoxetine; MPH comparison (n = 20) | 12 weeks | Stroop Counting Task | Over time and similar to MPH, reaction time during incongruent trials |
Over time relative to MPH, greater in left dorsal ACC and DLPFC activity and smaller in left IFG activity |
Atomoxetine (T0, T1) vs. methylphenidate (T0, T1) | Incongruent vs. congruent |
| Wagner et al. (66)D | Major depression | 8 | – | 20; T0 | Open-label trial | Reboxetine | 6 weeks | Stroop color-word task | Over time, larger in reaction time for incongruent trials, relative to congruent trialsF
|
– | – | – |
| Friedman et al. (84) | SCZ (atypical antipsychotics) | 5 | 3 | – | Randomized double-blind PLC-controlled design | Atomoxetine adjunctive treatment; PLC (n = 3) | 8 weeks | n-back | – | At T1 relative to PLC patients, left DLPFC activity |
Atomoxetine (T1) vs. PLC (T1) | 2-back + 3-back vs. 0-back |
| α2A adrenergic receptor agonists | ||||||||||||
| Bedard et al. (85) | ADHD (pediatric) | 12 | 13 | – | Randomized double-blind PLC-controlled trial | Guanfacine | 6–8 weeks | Go/No Go | No differences in task performance (over time) | Over time relative to PLC patients, n.s. differences | Guanfacine (T0, T1) vs. PLC (T0, T1) | Go vs. No Go |
*Appeared; not present at T0, present at T1.
†Remained; present at T0 and T1.
, increased or higher; , decreased or lower; T0, baseline; T1 and T2, follow-up; CTRL, healthy volunteers; PLC, placebo-treated; MPH, methylphenidate; FC, functional connectivity; DMN, default mode network. Psychiatric disorder: ADHD, attention-deficit/hyperactivity disorder; BD, bipolar disorder; OCD, obsessive–compulsive disorder; FEP, first-episode psychosis; SCZ, schizophrenia.
Brain regions: ACC, anterior cingulate cortex; DLPFC, dorsolateral prefrontal cortex; DMPFC, dorsomedial prefrontal cortex; FC, frontal cortex; IFG, inferior frontal gyrus; IPL, inferior parietal lobule; IPS, intraparietal sulcus; M1, primary motor area; MFC, medial frontal cortex; MFG, medial frontal gyrus; OFC, orbitofrontal cortex; PC, parietal cortex; PFC, prefrontal cortex; SEF, supplementary eye fields; SFG, superior frontal gyrus; SMA, supplementary motor area; SPL, superior parietal lobule; VLPFC, ventrolateral prefrontal cortex; VMPFC, ventromedial prefrontal cortex.
A,BIdentical sample. C,DPart of same investigation. E,FSignificant effect/association in combined sample. GConsists of ACC, DLPFC, premotor cortex, and PC. HConsists of DLPFC, IPL, and frontopolar cortex.