In adults with unipolar or bipolar depression and suicidal ideation, six intravenous ketamine infusions over two weeks produced significant reductions in suicidal ideation. Mediation analyses showed these anti‑suicide effects were partially mediated by reductions in depressive symptom severity and by improved processing speed, but not by other cognitive domains.
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Objective
Prior research has shown that ketamine has anti-suicide effects. Additional evidence also suggests that ketamine may offer pro-cognitive effects. Herein, we propose that the anti-suicide effects of ketamine are partially mediated via pro-cognitive effects. We aimed to determine whether improvement in cognitive function mediated change in suicidal ideation was associated with ketamine treatment.
Methods
Unipolar or bipolar depressive patients (n = 86) with suicidal ideation received six infusions of ketamine (0.5 mg/kg) over 2 weeks. The current severity of suicidal ideation and depression symptoms were assessed with the Beck Scale for Suicide Ideation (SSI) and the Montgomery–Asberg Depression Rating Scale (MADRS), respectively, at baseline, days 13 and 26. Cognitive domains, including processing speed, working memory, visual learning, and verbal learning were measured with the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery at the same time points.
Results
Mediation analysis showed a significant total effect of ketamine treatment on SSI score (coef = –1.853, 95%CI [–2.2, –1.5]). The direct and total indirect (MADRS total score and any of cognitive domains) effects of ketamine on suicidal ideation both were statistically significant (direct: coef = –1.064 to –1.352; total indirect: coef = –0.501 to –0.788). MADRS total score and processing speed (but not other cognitive domains) were significant partial mediators of the association between ketamine treatment and improvements in suicidal ideation.
Conclusion
Depressive symptoms severity and processing speed performance partially mediated improvements in suicidal ideation after repeated ketamine infusions in persons with unipolar or bipolar depressive disorder.
Suicide is a major global public-health problem and is frequently associated with mood disorders such as major depressive disorder (MDD) and bipolar depression. Conventional treatments (antidepressants, cognitive behavioural therapy, electroconvulsive therapy) can reduce suicidal ideation but typically require weeks to take effect, leaving many patients at persistent risk. Over the past two decades, repeated evidence from randomised trials has shown that subanesthetic doses of ketamine, an NMDA receptor antagonist, produce rapid antidepressant and anti-suicide effects, sometimes within hours. Concurrently, cognitive dysfunction (notably in processing speed, working memory, executive function and decision-making) is recognised as a core feature of depression and has been linked to suicidal vulnerability. Preliminary reports have also suggested that ketamine may produce pro-cognitive effects in some cognitive domains. Z. and colleagues set out to test the hypothesis that ketamine's anti-suicide effects are at least partly mediated by pro-cognitive effects. Specifically, the authors aimed to determine whether improvements in depressive symptoms and/or in selected cognitive domains (processing speed, working memory, visual learning and verbal learning) mediated changes in suicidal ideation after six intravenous ketamine infusions given over 2 weeks to adults with unipolar or bipolar depression and baseline suicidal ideation. They also examined baseline predictors of anti-suicide response to repeated ketamine infusions.
This analysis used data from a larger single-centre, open-label study of intravenous ketamine in adults with MDD or bipolar depressive disorder. From the larger cohort, 86 participants who received six ketamine infusions and completed clinician-rated measures at baseline and day 13 were included in the present mediation analysis. Eligible participants were adults (≥18 years) meeting DSM-5 criteria for MDD or bipolar depression, with moderate-to-severe depressive symptoms (HAMD-17 ≥ 17) and evidence of suicidal tendency (Beck Scale for Suicide Ideation (SSI) part I score ≥ 2 at screening). Exclusion criteria included alcohol or substance dependence, unstable medical conditions, psychotic symptoms and recent mania/hypomania (within 6 months for bipolar participants). Participants continued their prescribed psychotropic medications at stable doses during the 2-week infusion period. All participants received six adjunctive intravenous infusions of ketamine hydrochloride at 0.5 mg/kg administered over 40 minutes on a Monday–Wednesday–Friday schedule across two weeks. Vital signs were monitored during and after each infusion. Clinical assessments occurred at baseline, 1 day after the sixth infusion (day 13) and 14 days after the sixth infusion (day 26). Primary measures were clinician-rated depressive symptoms (Montgomery–Åsberg Depression Rating Scale, MADRS) and current suicidal ideation (SSI part I). Cognitive function was assessed with four domains drawn from the MATRICS Consensus Cognitive Battery (MCCB): processing speed (Category Fluency, Trail Making A, BACS), working memory (WAIS-III letter–number sequencing; WMS-III Spatial Span), visual learning (BVMT-R) and verbal learning (HVLT-R). Domain scores were standardised to T scores (mean 50, SD 10). For statistical analysis the authors used linear mixed models to test change over time in MADRS, SSI and cognitive domain scores, with measurement point (baseline, day 13, day 26) as a factor and covariates including age, sex, education, illness duration, BMI, primary diagnosis and concomitant medications (mood stabiliser/benzodiazepine/antipsychotic co-prescription; one versus two antidepressants). Mediation was tested using PROCESS v2.15 in SPSS: measurement point served as the independent variable (X), SSI score as the dependent variable (Y), MADRS total score as the first mediator (M1) and each cognitive domain T score as the second mediator (M2) in serial mediation models. Covariates listed above were included. The authors report unstandardised coefficients and p-values. Finally, binomial logistic regression (forward LR) was used to identify baseline predictors of anti-suicide response and remission on the SSI at day 13.
The present data were obtained from a larger single-center open label study comprising a total of 136 adults patients with MDD or bipolar depressive disorder received six subanesthetic doses of ketamine. This study was approved by the Clinical Research Ethics Committee of the Affiliated Brain Hospital of Guangzhou Medical University and is registered on Chinese Clinical Trial Registry under the identifier ChiCTR-OOC-17012239. Eligibility criteria and treatment protocol have been outlined previously. Briefly, all the subjects were adults (age ≥ 18 years) male or female with a diagnosis of MDD or bipolar disorder supported by the Diagnostic and Statistical Manual of Mental Disorders (DSM-5.0) criteria; moderateto-severe depressive symptom severity assessed by the 17item Hamilton Depression Rating Scale (HAMD-17, total scores ≥ 17); and with a suicidal tendency confirmed by a Beck Scale for Suicide Ideation (SSI) part I score ≥ 2 at screening. Participants were excluded if they had a presence of alcohol or substance dependence or any serious or unstable medical conditions identified through physical examination, vital signs, weight, electrocardiogram, blood tests, and urinalysis. Participants were also excluded if had psychotic symptoms or bipolar depressive patients had a mania or hypomania episode in the preceding 6 months. All the participants received six infusions of intravenous ketamine (0.5 mg/kg) over 2 weeks (infusion on Monday-Wednesday-Friday). Ketamine was administered as an adjunctive to current psychotropic medications which were required to maintain the same dose during the 2-week period. Ketamine hydrochloride injection mixed with 0.9% sodium chloride injections was administered by IV pump over 40 min by a study physician and research nurse. Vital signs (blood pressure, pulse, and oxygen saturation) were monitored throughout the infusion and post-infusion to ensure a return to pre-infusion levels. Additional detailed information regarding these participants has been described in our previous studies.
Depressive symptoms, suicidal ideation, and cognitive function were assessed at baseline, 1 day following the sixth infusion (i.e., day 13), and again 14 days following the sixth infusion (i.e., day 26). The Montgomery-Asberg Depression Rating Scale (MADRS) was used to characterize depressive symptoms by clinicians. The total scores range 0-60 and higher scores indicated more severe depressive symptom. Current severity of suicidal ideation was assessed via the SSI part I, a 5item scale rating from 0 (least severe) to 2 (most severe) and score range 0-10 (. There were seven cognitive domains in the MCCB, but four of them, including processing speed [using the Category Fluency test, Trail Making A test, and Brief Assessment of Cognition in Schizophrenia (BACS)], working memory [using WAIS-III, letter-number sequencing (LNS) subtest, WMS-III, Spatial Span], visual learning (using Brief Visuospatial Memory Test-Revised, BVMT-R), and verbal learning (using Hopkins Verbal Learning Test-Revised, HVLT-R) were selected in the study. Each domain score was standardized to a T score with a mean of 50 and a standard deviation of 10.
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Sample and retention: Of 104 patients with MDD or bipolar depression and suicidal ideation who received ketamine, 86 patients completed six infusions and had MADRS, SSI and MCCB data at baseline and day 13; 10 participants (11.6%) did not complete the day 26 visit. Clinical and cognitive change over time: Six ketamine infusions were associated with significant reductions in SSI and MADRS scores. Reported SSI means (± SD) were 4.7 ± 3.0 at baseline, 0.9 ± 1.9 at day 13 and 1.0 ± 1.9 at day 26 (F = 79.643, P < 0.001). The authors also report improvements in certain cognitive domains (processing speed and verbal learning) after treatment, although full domain-wise statistics are not reproduced in the extracted text. Mediation analysis: The overall (total) effect of ketamine treatment (measurement point) on SSI score was significant (coef = -1.853, 95% CI [-2.2, -1.5]). When serial mediation models included MADRS as M1 and each cognitive domain as M2, the authors report that both direct and total indirect effects were statistically significant for models with processing speed, working memory, verbal learning and visual learning entered as M2 (direct effects ranged approximately from coef = -1.064 to -1.352; total indirect effects ranged approximately from coef = -0.501 to -0.788 with respective 95% CIs). Despite these findings, the authors concluded that, of the tested variables, MADRS total score and processing speed T score were significant partial mediators of the relationship between ketamine treatment and improvements in suicidal ideation. In contrast, working memory, verbal learning and visual learning did not demonstrate a statistically significant mediational role in the fully specified models. Predictors of response and remission: On the SSI at day 13 the response rate was 80.2% and the remission rate was 64.0%. In logistic regression models that included the four baseline cognitive domains, baseline processing speed was the only significant predictor of achieving an anti-suicide response (B = 0.062, P = 0.028) and also predicted remission when cognitive domains alone were entered (B = 0.075, P = 0.004). When baseline MADRS and SSI scores were included alongside the cognitive domains in the remission model, baseline SSI score (B = -0.275, P = 0.001) remained a significant predictor and baseline processing speed was excluded from the final model. Other notes: The extracted text does not report adverse event rates or detailed domain-by-domain numerical changes for all cognitive measures, nor does it reproduce the full tables or figures referenced by the authors.
Z. and colleagues interpret their findings as indicating that six subanesthetic ketamine infusions in adults with unipolar or bipolar depression and baseline suicidal ideation were associated with rapid improvements in mood, reductions in suicidal ideation and pro-cognitive effects (notably processing speed and verbal learning). Their mediation analyses led them to conclude that the anti-suicide effect of repeated ketamine infusions was partially mediated by improvements in overall depressive symptoms (MADRS) and by improvements in processing speed, while measures of working memory, verbal learning and visual learning did not significantly mediate changes in suicidal ideation in the fully specified models. The authors note that greater baseline processing speed predicted a higher likelihood of anti-suicide response to repeated ketamine infusions. The authors frame these findings within distinctions between cold cognition (emotion-independent functions such as memory, attention and executive function) and hot cognition (emotion-laden processes such as rumination and suicidal ideation). They suggest that ketamine may modulate both hot and cold cognitive processes, and that pro-cognitive effects may contribute to reductions in suicidal ideation. Mechanistic discussion highlights ketamine’s glutamatergic modulation, increased AMPA throughput, and downstream effects on BDNF and mTOR signalling that promote synaptogenesis; the authors also cite neuroimaging findings (changes in prefrontal connectivity, hippocampal, amygdala and nucleus accumbens volumes) as plausible substrates linking ketamine’s antidepressant, anti-suicide and procognitive effects. The authors acknowledge several important limitations. The study was a single-arm, open-label design without a control group, which permits expectation bias in clinician- and patient-rated outcomes. Only four cognitive domains were assessed from the MCCB and the study did not include dedicated decision-making tasks (e.g. Iowa Gambling Task), limiting the assessment of cognitive functions most consistently linked to suicidality. Participants with severe suicidal ideation or recent suicidal behaviour were excluded for safety, so results cannot be generalised to those at highest acute risk and cannot be extrapolated to suicidal behaviours (attempts or completion). Concomitant psychiatric medications were maintained and could confound cognitive and clinical changes, limiting applicability to medication-free patients. Finally, the authors emphasise that the study focused on reductions in suicidal ideation and that reductions in ideation do not necessarily predict reductions in suicidal behaviour; they recommend future work that assesses behavioural outcomes and integrates neuroimaging to clarify mechanisms.
Data were analyzed with IBM Statistical Package for the Social Sciences (SPSS) statistical software for Windows, version 22. All the tests were two-sided with statistical significance at p < 0.05. Change in MADRS total score, SSI score, and the four cognitive domain performance following ketamine treatment was assessed using a linear mixed model with measurement point (i.e., baseline, days 13 and 26) as factors. The patients' characteristics including age, gender, education, duration of illness, body mass index (BMI), and concomitant medications (combined use of mood stabilizer/benzodiazepine/antipsychotic or not, and use of one or two antidepressants) were included as covariates. Then, mediation analysis using the process v2.15 in SPSS was used to investigate whether overall depressive symptom and cognitive function mediated the anti-suicide effect in patients following six ketamine infusions. In this model measurement point (i.e., baseline, days 13 and 26) was the independent variable (X), anti-suicide effect (i.e., SSI score) was the dependent variable (Y), depressive symptom severity (i.e., MADRS total score) was the first mediator (M1), and cognitive function (i.e., processing speed, working memory, visual learning, verbal learning T score) was the second mediator (M2). Patients' characteristics, including age, gender, education, duration of illness, BMI, primary diagnosis, and concomitant medications (combined use of mood stabilizer/benzodiazepine/antipsychotic or not, and use of one or two antidepressants) were treated as covariates. Unstandardized beta coefficients (Coef) and P-value are reported. Finally, a binomial logistic regression using forward LR method was completed to determine the effect of baseline
The project included 104 MDD or bipolar depression with suicidal ideation received ketamine treatment, and 86 of them received six infusions and completed MADRS, SSI, and MCCB at baseline and day 13 whose data were included in this study. In total, 11.6% of them (N = 10) failed to complete the final visit (day 26). Demographic and clinical characteristics are reported in Table.
Six infusions of ketamine were significantly associated with reductions in SSI score and MADRS total score, which have been reported previously. There was a significant main effect of ketamine treatment on SSI score (baseline: 4.7 ± 3.0; day 13: 0.9 ± 1.9; day 26: 1.0 ± 1.9; F = 79.643, P < 0.001; Path analysis was conducted to explore whether improvements in overall depressive symptom severity and cognition acted as the mediator between the ketamine treatment and improvements in suicidal ideation. There was a significant total effect of ketamine treatment on SSI score (coef = -1.853, 95%CI [-2.2, -1.5]). The direct and total indirect effects of ketamine on suicidal ideation both were statistically significant: processing speed as M2 (direct: coef = -1.064, 95%CI [-1.5, -0.6]; total indirect: coef = -0.788, 95%CI [-1.2, -0.4]), working memory as M2 (direct: coef = -1.270, 95%CI [-1.8, -0.8]; total indirect: coef = -0.583, 95%CI [-1.0, -0.2]), verbal learning as M2 (direct: coef = -1.352, 95%CI [-1.8, -0.9]; total indirect: coef = -0.501, 95%CI [-0.9, -0.1]), and visual learning as M2 (direct: coef = -1.300, 95%CI [-1.8, -0.8]; total indirect: coef = -0.552, 95%CI [-0.9, -0.2]). MADRS total score and processing speed T score were significant partial mediators of the relationship between ketamine treatment and improvements in suicidal ideation, however, the foregoing effect was not demonstrated in measures of working memory, verbal learning, or visual learning (Tableand Figure).
The response rate on the SSI at day 13 was 80.2%, and remission rate was 64.0%. In the binomial logistic regression model of responder outcome, when the four baseline cognitive domains were included as independent variables, baseline speed processing was the only variable that predicted achieving an anti-suicide response to six infusions of ketamine (B = 0.062, P = 0.028). When baseline MADRS score and SSI score, as well as the four baseline cognitive domains were included as independent variables simultaneously in the responder outcome model, the statistical results did not change, baseline processing speed still was the only significant predictor of the anti-suicide response (B = 0.062, P = 0.028). In the binomial logistic regression model of remitter outcome, when the four baseline cognitive domains were included as independent variables, only baseline processing speed was a significant predictor of remission (B = 0.075, P = 0.004). When baseline MADRS score and SSI score, as well as the four baseline cognitive domains were included as independent variables simultaneously in the remitter outcome model, baseline SSI score was a significant predictor of remission (B = -0.275, P = 0.001), while baseline speed processing was excluded in the model.
Herein, we observed six infusions of ketamine in unipolar or bipolar depressive disorders with suicidal ideation were associated with improved mood, suicidal ideation, and cognitive function (i.e., processing speed, verbal learning). Mediational analysis indicated that the anti-suicide effects were partially mediated by improvements in depressive symptom and processing speed. The mediational effect of working memory, verbal learning, or visual learning on the change in SSI was not statistically significant. Herein, we speculate that for some individuals, ketamine's anti-suicide effects may be subserved by improvements in processing speed. Baseline processing speed was a significant predictor of anti-suicide effect, indicating greater baseline processing speed performance was associated with an increase likelihood of achieving anti-suicide effect over six ketamine infusions. Cognitive function in mood disorder can be broadly categorized as cold cognition and hot cognition. The former refers to information processing in the absence of any emotional influence, yet the latter is influenced by emotion. Usually, cold cognition is considered to include memory, attention, executive function, working memory while hot cognition includes catastrophic reactions to real and/or perceived slights, anhedonia, suicidal ideation, negativistic rumination, negative recall bias, and disproportionate attention to negative stimuli. Over the past years, an increasing number of literatures have established that cognitive deficits are closely related to suicidality. In subgroups of individuals with suicidal ideation and behavior represent deficits in cognitive function (i.e., executive function, impulsivity, attention). A conceptual framework of cognitive function in mood disorder was provided by McIntyre and colleagues in a review indicating implicit suicidal ideation as a domain of hot cognition. These give us indication that improvements in cognitive function may be closed to the anti-suicide effect by the antidepressant treatment, with no exception to ketamine. The hot and cold cognitive functions could benefit from subanesthetic dose of ketamine. Ketamine's benefit on hot cognition is embodied in the improvement in suicidal ideation, anhedonia, and overall mood symptoms. Furthermore, ketamine's enhancement in positive bias and decline in negative emotional perception in MDD further supports its favorable effect on hot cognition. The cold cognition benefit is implicated by improvement in working memory, visual memory, and processing speed after ketamine treatment, although some studies reported it was mediated by depressive symptom improvement. Our results suggested that repeated ketamine infusions have a pro-cognitive effect independent of decrease in depression severity. Mediational analysis indicated that the improvement in the processing speed was partly independent of decrease in the MADRS score, and the direct effect (coef = 2.732) was greater than the indirect effect (coef = -0.118 × -9.968 = 1.220). The foregoing is in accordance with the results of two other studies with repeated ketamine infusions. McIntyre et al. reported improvement in Trail Making Test-B, measurement processing speed and executive function, was fully independent of improvement in depressive symptom after four infusions in individuals with MDD and bipolar depression. Shiroma et al.observed a mood independent pro-cognitive effect on processing speed, attentional set-shifting and spatial working memory among patients with TRD following six doses of ketamine treatment. The results of mediation analysis suggested that the specific effect of ketamine on suicidal ideation also was positively related to pro-cognitive effect. In addition, the present results showed ketamine's specific decrease in suicidal ideation was larger in individuals with greater processing speed at baseline. In a randomized controlled trial of a single infusion of ketamine, Price et al. reported patients with higher severity of baseline suicidal cognition manifest greater anti-suicide effects, which were partly mediated by a decrease in non-suicide-related depressive symptom. In a naturalistic follow-up study of participants with suicidal ideation found that better cognitive flexibility, assessed by the Wisconsin Card Sorting Test which also reflected executive function, predicted less suicidal ideation after 6 months. Our previous clinical study found early increase in levels of kynurenic acid, an NMDA receptor agonist leading to neuroprotection by elevation of extracellular glutamate, could predict anti-suicide response following six infusions of ketamine treatment. This is partially supported that patients who have a higher intrinsic "restorative" capacity of neuronal plasticity may be more likely to benefit from ketamine. In addition, the neuromechanism of ketamine on brain may be involved in the relationship between its pro-cognitive effects and anti-suicide as well as antidepressant effects. Ketamine as an NMDA receptor agonist has a unique mechanism of action involving glutamate modulation via increased NMDA and αamino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor throughput, leading to potentiation of BDNF and mechanistic target of rapamycin (mTOR) signaling pathways, and these finally contribute to the augmented synaptogenesis and synapse stabilization. Ketamine's glutamatergic modulation of numerous brain regions and neural circuits, as shown in neuroimaging studies, was considered to involve in its antidepressant and anti-suicide action, and also procognitive effect. The prefrontal cortex (PFC) global connectivity could be normalized in responders and the extent of the PFC global connectivity increase was associated with response after a single dose of ketamine. Another study found increased hippocampal volumes and decreased nucleus accumbens volumes 24 h post-single dose of ketamine. Our previous study also showed increased volumes of the left amygdale and the right hippocampus after six infusions of ketamine. These brain regions and neural circuits correlated to ketamine's treating response also involve hot and cold cognitive functions in patients with MDD, as mentioned in the previous study. Herein, we propose that ketamine's antidepressant effects are mediated, in part, by targeting neural circuits that subserve the relevant to cognitive processing and emotional processing. It stands to reason that given ketamine's known effect on neural structures and functions, its anti-suicide effects may be in part via pro-cognitive effects. The results from this study provide some clues for future work aimed to understand the neural mechanism for the effect of ketamine on suicidal ideation, and these evidences augmented with neuroimaging would be an important pathway for future work. The present findings should be considered the following limitations. First, the results were obtained from a single arm open label study without a control arm. This may introduce expectation bias both to assessments from the clinician and patients. Second, several lines of evidence suggested that executive function, particularly the decision-making was related to suicidality. Decision-making performance was measured usually using the Iowa Gambling Task (IGT), and poorly performed by patients with current or history of suicide attempt/ideation was observed compared with the healthy controls. This study only assessed four cognitive domains, although the Category Fluency test, Trail Making A test, and BACS could well reflect the executive function, lack of decision-making tasks was a significant limitation to describe a complete association between cognition and suicidal ideation. This limitation led to an incomplete relationship between cognitive function and anti-suicide effects of ketamine. Third, patients with severe suicidal ideation or suicidal behavior were excluded for safety reason, therefore, making it difficult to generalize present results to that population. Thus, our findings should not be extrapolated to outcomes of suicidal behavior, particularly attempted or completed suicide. Fourth, all subjects were taking their prior prescribed medications, including benzodiazepine, lithium, and antipsychotics, which may moderate changes in cognition. While changes to medication were not permissible during the study, the effect of psychiatric medication could confuse the observed outcomes. Therefore, the current findings could not be extrapolated to medication-free patients. An additional limitation is we were looking at reduction in suicidal ideations future studies should be looking at reductions in suicide and we do not know if reductions in suicidal ideations would necessarily predict reduction in suicide.