Table 1.
Summary of studies.
| Randomized-Controlled Trials | ||||||
| Author | Treatment | Description | N | Endpoints | Results | Post-TBI Disorder |
| Ansari et al., 2014 [26] | Sertraline | 80 adult male patients with post-TBI depression. 40 patients given sertraline 50 mg/day, 40 patients given placebo. | 80 | PHQ-9 | Sertraline group showed significant improvement in mood and QOL domains (PHQ-9: 14.88 ± 3.60 vs. 5.33 ± 2.98, p = 0.040). | Depression |
| Ashman et al., 2009 [27] | Sertraline | 10-week program studying 52 patients with TBI and MDD treated with sertraline or placebo. | 52 | Ham-D | Both groups significantly improved (59% treatment group, 32% placebo group) with Ham-D reduction by 50%. | Depression |
| Banos et al., 2010 [28] | Sertraline | Three-month study of 99 subjects with moderate/severe TBI randomized to sertraline 50 mg (n = 49) or placebo (n = 50). | 99 | WMS, TMT, NFI | No sertraline treatment effect was observed for cognitive performance. | Cognition |
| Jorge et al., 2016 [29] | Sertraline | 94 patients administered sertraline vs. placebo at 100 mg/day for 24-weeks. | 94 | MINI | Number needed to treat to prevent depression after TBI at 24-weeks is 5.9 for sertraline vs. placebo (p = 0.03). Sertraline effects were well-tolerated. | Depression |
| Lee et al., 2005 [30] | Sertraline | Four-week study of 30 patients with MDD treated with sertraline 25–100 mg/day (n = 10), methylphenidate 5–20 mg/day (n = 10), or placebo (n = 10). | 30 | Ham-D, ESS, RPQ | Methylphenidate and sertraline showed improvement in depressive symptomatology. Methylphenidate and placebo showed improvement in cognitive function vs. sertraline. | Cognition, Depression, PCS |
| Meythaler et al., 2001 [31] | Sertraline | Two-week study of 11 patients with severe TBI post MVA. Patients received sertraline 100 mg/day or placebo. | 11 | OL, ABS, GOAT | No effect of sertraline treatment was identified. | Cognition |
| Novack et al., 2009 [32] | Sertraline | One-year study of 99 non-depressed TBI subjects received either sertraline 50 mg/day (n = 49) or placebo (n = 50). | 99 | Ham-D, NFI | Placebo group developed more depressive symptoms (p = 0.023). Sertraline associated with decreased neurobehavioral functioning. | Depression |
| Rapoport et al., 2010 [33] | Citalopram | 21 patients in remission from depression after TBI were randomized to same-dose citalopram (n = 10) or placebo (n = 11) and followed for 40 weeks. | 21 | Ham-D | Relapse occurred in 11 subjects (52.4%). Treatment groups did not differ in relapse rates (citalopram: 50% vs. placebo: 54.5%; p = 0.835). This trial suggested limitations of pharmacotherapy in the prevention of MDD relapse following TBI. | Depression |
| Open-Label Studies | ||||||
| Author | Treatment | Description | N | Endpoints | Results | Post-TBI Disorder |
| Dolberg et al., 2002 [34] | Fluoxetine, Citalopram, Paroxetine, Sertraline | 17 TBI patients were given SSRIs. All complained of sexual dysfunction which was resolved with mianserin (tetracyclic anti-depressant). | 17 | Occurrence of sexual dysfunction | SSRI use associated with sexual dysfunction. 15 patients (88%) reported improvement of symptoms with mianserin. | Sexual dysfunction |
| Fann et al., 2000 [35] | Sertraline | 15 patients with mild TBI within the past 3–24 months. Placebo in-run design where all subjects received 1-week placebo followed by 8-week single-blind course of sertraline. | 15 | Ham-D | Sertraline significantly improved depressive symptoms (Ham-D 25.0 ± 4.4 to 7.2 ± 5.3 at Week 8 (p < 0.001). There was improvement of cognitive functions in psychomotor speed, cognitive efficiency, flexible thinking, and recent memory ability. | Cognition, Depression |
| Horsfield et al., 2002 [36] | Fluoxetine | 5 TBI patients with no to moderate depressive symptoms followed for 8 months. | 5 | TMT, AMT, WAIS-III, USCREMT, MMSE, Ham-D | Fluoxetine improved mood and performance on some but not all cognitive measures. More studies needed. | Cognition |
| Lanctot et al., 2010 [37] | Citalopram | 90 patients with major depressive episode following TBI in a six week study also examining six serotonergic SNPs. | 90 | Ham-D | MTHFR and BDNF SNPs predicted greater treatment response (r2 = 0.098, F = 4.65, p = 0.013). The 5HTTLPR SNP predicted greater occurrence of adverse events (r2 = 0.069, F = 5.72, p = 0.020). Serotonergic SNPs may associate with tolerability and efficacy of SSRIs. | Depression |
| Luo et al., 2015 [38] | Citalopram, prednisone | 68 patients with depression following TBI. | 68 | Glasgow Coma Scale, Ham-D | Over 60% of patients who did not respond to psychotherapy alone (60/68) responded to citalopram treatment. Patients with hypocortisolism also were treated with prednisone | Depression |
| Muller et al., 1999 [39] | Paroxetine, Citalopram | 26 patients with brain damage and pathological crying. Only 2 TBI related. | 2 | Clinical interviews related to pathological crying | Both paroxetine and citalopram improved symptoms for 24/26 (92.3%) patients within 3 days. | Emotional incontinence |
| Perino et al., 2001 [40] | Citalopram, Carbamazepine | 20 patients with MDD following TBI were divided into two groups: group A with recent TBI (<6 months), and group B with long-term TBI (24–36 months). | 20 | BPRS | BPRS and CGI scores of the total sample showed significant improvement between baseline and 12 weeks (BPRS baseline: 62.3 ± 17.6 vs. 12 weeks: 51.7 ± 12.8; p < 0.05), (CGI severity-scale baseline: 4.4 ± 1.1 vs. 12 weeks: 3.4 ± 0.8; p < 0.005). No group effects were observed. | Depression |
| Rapoport et al., 2008 [41] | Citalopram | 54 patients with mild to moderate depression post-TBI. 29 patients underwent 6 week fixed dose treatment; 36 underwent 10-week flexible dose treatment. | 54 | Ham-D | The mean Ham-D at baseline and 6 weeks were 23.66 (SD 6.8) and 16.30 (SD 9.3), respectively (p < 0.0001). The mean Ham-D at 10 weeks was 12.96 (SD 7.9) (p < 0.0001). Treatment showed significant reduction in depressive symptoms. | Depression, PCS |
| Turner-Stokes et al., 2002 [42] | Sertraline | 27 patients with depression due to brain injury - 5 due to TBI. | 27 | BDI-II | The BDI-II was assessable in 17/21 patients, showing a mean improvement of 14.5 ± 9.7 (p < 0.001). | Depression |
| Case Reports | ||||||
| Author | Treatment | Description | N | Endpoints | Results | Post-TBI Disorder |
| Hensley et al., 2010 [43] | Sertraline, Paroxetine | 22-year-old female with MVA-related TBI. | 1 | -- | Treatment of alcohol withdrawal related anxiety with SSRIs led to akathisia that resolved with TCA treatment. | Akathisia, Anxiety |
| Nahas et al., 1998 [44] | Fluoxetine | 21-year-old male with MVA-related TBI leading to pathological crying. | 1 | -- | Fluoxetine treatment led to complete resolution of pathological crying within 1 week. | Emotional incontinence |
| Patterson et al., 1997 [45] | Sertraline, Trazodone | 43-year-old male with TBI following fall prescribed trazodone for chronic pain and sleep disturbance, and fluoxetine for treatment of depression. | 1 | -- | Fluoxetine addition led to dysarthria that resolved with fluoxetine discontinuation. | Depression |
| Scheutzow et al., 1999 [46] | Sertraline | 60-year-old male with TBI following MVA experiencing panic attacks. | 1 | -- | Sertraline improved mood and appetite but did not resolve all panic and anxiety symptoms. | Anxiety, Panic |
| Slaughter et al., 1999 [47] | Sertraline | 2 male patients with Kluver-Bucy syndrome from MVA related TBI. | 2 | -- | Resolution of symptoms (hyperorality, hyper-sexuality) with high dose SSRI similar to OCD. | Emotional incontinence, OCD |
| Sloan et al., 1992 [48] | Fluoxetine | 28-year-old assault victim with TBI related pathological laughter, dysarthria and hemiataxia. | 1 | -- | Fluoxetine plus speech therapy helped with emotional lability grading and was well tolerated. | Emotional incontinence |
| Spinella et al., 2002 [49] | Fluoxetine, Buspirone, Ginkgo Biloba | 42-year-old female with mild TBI following MVA. | 1 | -- | Herbal supplements plus SSRI led to hypomania, highlighting the need to study SSRI interactions with other medications following TBI. | Depression |
| Stanislav et al., 1999 [50] | Sertraline | 24-year-old with severe TBI following MVA presenting with PTSD. | 1 | -- | Clinical case of dystonia following SSRI treatment. | Depression, PTSD |
| Stengler-Wenzke et al., 2002 [51] | Fluoxetine | 18-year-old male with severe TBI following MVA. | 1 | -- | Fluoxetine treatment drastically reduced OCD symptoms and increased quality of life. | OCD |
| Workman et al., 1992 [52] | Sertraline, Lithium | 56-year-old female with severe TBI from fall requiring bilateral frontal lobectomies. | 1 | -- | Sertraline plus lithium treatment reduced patients Ham-D score from 15 to 4. Symptoms of mood lability and conceptual disorganization resolved. | Emotional incontinence |
| Wroblewski et al., 1992 [53] | Fluoxetine, Phenytoin | 23-year-old TBI patient with seizures following TCA treatment of depression. | 1 | -- | Resolution of seizures and improvement of mood with fluoxetine treatment with phenytoin. | Depression |
| Review Articles | ||||||
| Author | Treatment | Description | N | Endpoints | Results | Post-TBI Disorder |
| Fann et al., 2009 [54] | Review | -- | -- | -- | Serotonergic system modulation through antidepressants has high tolerability in treatment of TBI patients with depression. | General |
| Fleminger et al., 2003 [55] | Review | -- | -- | -- | Three- to four-fold increase in suicide rates following TBI, suggested heightened surveillance for TBI subpopulations. Little conclusive evidence for SSRI use highlights need for longitudinal care. | Depression |
| Jorge et al., 2003 [56] | Review | -- | -- | -- | Mood disorders are frequent complications of TBI and are often overlooked. Further research is needed for the neuropsychiatric sequelae of these disorders. | Anxiety, OCD, Panic |
| Lee et al., 2003 [57] | Review | -- | -- | -- | Up to 60% of TBI patients are affected by neuropsychiatric sequelae. Drugs exist to treat specific conditions but RCTs are needed to delineate true treatment effects following TBI. | Anxiety, Cognition, Depression |
| Lombardi et al., 2008 [58] | Review | -- | -- | -- | Symptomatic treatment studies that understand and address underlying neurobiological recovery processes are needed. | Cognition, PCS |
| Silver et al., 2009 [59] | Review | -- | -- | -- | Depression and cognitive impairment are common neuropsychiatric symptoms after TBI. Several small studies suggest that SSRIs and tricyclic antidepressants may improve depression in this population. | Cognition, Depression |
| Tenovuo et al., 2006 [60] | Review | -- | -- | -- | Lack of large scale RCTs place burden on clinician for pharmacologic treatment of TBI-related depression. | Cognition |
| Wheaton et al., 2011 [61] | Review | -- | -- | -- | Pharmacological treatments that are administered to adults in the postacute stage (≥4 weeks) after TBI have the potential to reduce persistent cognitive and behavioral problems. Sertraline can possibly impair cognition and psychomotor speed. | Cognition |
| Zafonte et al., 2002 [23] | Review | -- | -- | -- | Limited studies exist among patients with TBI, but serotonin agents including SSRIs seem to be effective for a variety of behavioral disorders. Care should be used when combining agents, and rapid withdrawal should be avoided. | Anxiety, Cognition, Depression |
ABS = Agitated Behavioral Scale; AMT = attentional motor task; BDI-II = Beck Depression Inventory, Second Edition; BPRS = Brief Psychiatric Rating Scale; ESS = Epworth Sleepiness Scale; GCS = Glasgow Coma Scale; Ham-D = Hamilton Depression Rating Scale; GOAT = Galveston Orientation and Amnesia Test; MDD = major depressive disorder; MINI = Mini-International Neuropsychiatric Interview; MMSE = Mini-Mental State Examination; MVA = motor vehicle accident; NFI = Neurobehavioral Functioning Inventory; OCD = Obsessive Compulsive Disorder; OL = Orientation Log; PHQ-9 = Patient Health Questionnaire-9; RPQ = Rivermead Post-Concussional Symptoms Questionnaire; SNP = single nucleotide polymorphism; SSRI = selective serotonin reuptake inhibitor; TBI = traumatic brain injury; TCA = tricyclic antidepressant; TMT = Trailmaking Test; USCREMT = University of Southern California Repeatable Episodic Memory Test; WAIS-III = Wechsler Adult Intelligence Test, Third Edition; WMS = Wechsler Memory Scale.