Cognitive effects of creatine monohydrate adjunctive therapy in patients with bipolar depression: Results from a randomized, double-blind, placebo-controlled trial

Highlights

• Depressive episodes and cognitive impairments produce most of the dysfunctionality in bipolar disorder.

• Multiple lines of evidence strongly implicate the occurrence of mitochondrial dysfunction in bipolar disorder.

• This study was the first to investigate cognitive effects of creatine monohydrate supplementation on bipolar depression.

• Creatine monohydrate supplementation for 6 weeks was associated with improvement in verbal fluency in bipolar depression.

• Future studies on the cognitive-enhancing properties of creatine monohydrate in bipolar disorder should be undertaken.

Abstract

Background

Depressive episodes and cognitive impairment are major causes of morbidity and dysfunction in individuals suffering from bipolar disorder (BD). Novel treatment approaches that target clinical and cognitive aspects of bipolar depression are needed, and research on pathophysiology suggests that mitochondrial modulators such as the nutraceutical creatine monohydrate might have a therapeutic role for this condition.

Methods

Eighteen (N=18) patients with bipolar depression according to DSM-IV criteria who were enrollled in a 6-week, randomized, double-blind, placebo-controlled trial of creatine monohydrate 6 g daily as adjunctive therapy were submitted to neuropsychological assessments (Wisconsin Card Sorting Test, Digit Span subtest of the Wechsler Adult Intelligence Scale–Third Edition, Stroop Color-Word Test, Rey–Osterrieth complex figure test, FAS Verbal Fluency Test) at baseline and week 6.

Results

There was a statistically significant difference between the treatment groups of the change on the total scores after 6 weeks in the verbal fluency test, with improvement in the group receiving adjunctive treatment with creatine. We did not find significant differences between the groups of the changes on other neuropsychological tests.

Limitations

Small sample and lack of a control group of healthy subjects.

Conclusions

Our trial, which was the first to investigate the cognitive effects of creatine monohydrate on bipolar depression, indicates that supplementation with this nutraceutical for 6 weeks is associated with improvement in verbal fluency tests in patients with this condition.

Introduction

Cognitive dysfunction has been identified as a core feature of bipolar disorder (BD) and is present both in symptomatic and remitted states. Meta-analytic data indicate that patients with BD exhibit impairments in tests of attention, processing speed, explicit memory and various aspects of executive function (Quraishi and Frangou, 2002, Arts et al., 2008, Robinson et al., 2006, Torres et al., 2007, Bora et al., 2009). Some researchers have even proposed that BD involves a progressive neurodegenerative decline in cognitive function, and that it is associated with neuroprogression (Goodwin et al., 2008, Berk et al., 2011).

The greatest burden in the course of bipolar disorder are caused by the depressive episodes, which are frequently chronic or highly recurrent, as well as resistance to available treatments (Judd et al., 2002, Judd et al., 2003, Post et al., 2010). Moreover, longitudinal studies have suggested that depressive symptoms precede and predict memory decline in non-demented older adults, leaving open the possibility that depressive symptoms may contribute to cognitive decline in BD in the long-term (Zahodne et al., 2014).

The cognitive impairments in BD are associated with psychosocial dysfuntion (Depp et al., 2012a) and likely relate to depressive symptoms in a mutually amplifying fashion (Depp et al., 2016), producing most of the dysfunctionality in BD. Cognitive impairment seems to be more associated with unemployment, while depressive symptoms to lower productivity (Depp et al., 2012b).

Most available pharmacological treatments for BD may potentially lead to some degree of cognitive disturbance, which seems to increase with polytherapy and high doses. Verbal memory deficits were associated with polypharmacy, although patients with a more severe form of BD may need combination of several medications (Balanzá-Martínez et al., 2010). Furthermore, pharmacotherapy for BD can cause numerous physical side effects, such as drowsiness, rapid heartbeat and weight gain (Kemp et al., 2010; Kemp, 2014) and increase the risk of cardiovascular disease (Serretti et al., 2013, de Almeida et al., 2012).

Adverse effects of currently available treatments are commonly cited by patients as primary reasons for low adherence to them (Rakofsky et al., 2011). Many patients view psychotropics with skepticism (Benkert et al., 1997) and prefer to use natural products that are more consistent with their values and health-related beliefs (Astin, 1998). In this context, nutraceuticals (which may be defined as any substance which is considered a food, a part of a food, a vitamin, a mineral or an herb that aids in the prevention and/or treatment of a disease) (Kalra, 2003) may consist of an interesting option to be further explored in the treatment of bipolar depression. Evidence in the literature has grown in favor of the selective use of nutraceuticals in the treatment of mood disorders as well as of the relationship between dietary patterns and mental health (Sarris and Mischoulon, 2011; Sarris et al., 2016). Indeed, the medical burden on individuals with BD may be due in part to poor nutritional habits (Sylvia et al., 2011). The International Society for Nutritional Psychiatry Research has advocated for consideration of Medical Nutrition as a first-order specialty in the context of psychiatric practice and for the select use of evidence-based nutraceuticals as a mainstay of treatment, either as stand-alone therapies or as adjunctive interventions with psychotropic medications to augment treatment efficacy (Sarris et al., 2015).

Multiple lines of evidence strongly implicate the occurrence of mitochondrial and bioenergetic dysfunction in the pathophysiology of bipolar disorder (Clay et al., 2011, Nierenberg et al., 2013). Some currently available dietary supplements that act as modulators of mitochondrial function and cellular energy metabolism have been tested as potential treatments for BD (Sarris et al., 2011).

Creatine is a non-essential dietary component found primarily in meat and fish and also endogenously produced by the liver, kidneys and pancreas (Wyss and Kaddurah-Daouk, 2000). It is continuously transported from the blood and accumulated in the brain against the creatine concentration gradient that exists between brain and blood until a maximum tissue storage capacity is reached, with excess being eliminated as waste (Ohtsuki et al., 2002).

Oral supplementation of creatine monohydrate (which has a short elimination half-life, averaging just less than 3 h) can increase brain levels of creatine and phosphocreatine (PCr) over span time periods of several weeks (Dechent et al., 1999, Lyoo et al., 2003). This suggests that supplementation with this nutraceutical could mitigate bioenergetic abnormalities in mood disorders by providing additional substrate for the production of ATP. In fact, a double-blind placebo-controlled trial that included fifty-two female subjects with unipolar depression showed that supplementation with creatine monohydrate (5 g/d) for eight weeks as an augmentation of treatment with escitalopram was safe and effective (Lyoo et al., 2012).

Studies that suggest cognitive-potentiating effects of creatine supplementation encourage research on this strategy as a therapy for the cognitive deficits found in BD. Creatine (8 g/day for 5 days) was given to 24 young healthy volunteers in a double-blind placebo-controlled trial (Watanabe et al., 2002) and the performance of subjects was checked in serial mathematical calculations for 15 min followed by 5 min rest, and then another 15 min series. The authors found that the decrease in performance in the last 15 min was lower in the group supplemented with creatine, indicating alleviation of mental fatigue. Similarly, 45 vegetarian young adults who received 5 g/day of creatine for 6 weeks in a double-blind crossover placebo-controlled trial (Rae et al., 2003a) showed improved results in the backward digit span (a working memory test) and the Raven's Advanced Progressive Matrices. The improved performance in the backward digit span was confirmed in omnivores, with decreased BOLD (Blood Oxygen Level Dependent) effect in functional magnetic resonance imaging (fMRI) after 1 week of creatine supplementation (20 g/day for 5 days followed by 5 g/day for 2 days, N=22) (Hammett et al., 2010). Creatine supplementation (20 g/d for 7 days) also prevented the decline in attention that occurred during an acute oxygen deprivation test in a placebo-controlled crossover study with 15 volunteers (Turner et al., 2015). Furthermore, McMorris et al. (2006) submitted 19 subject to sleep deprivation for 24 h; 10 of these volunteers had received creatine (20 g/d for 7 days) and 9, placebo. Significant effects of pre-supplementation with creatine were observed after 24 h in improving cognitive measures of reaction time and working memory.

To our knowledge, there are no published studies in the literature that have investigated the clinical and cognitive effects of creatine supplementation on bipolar disorder. In view of the data outlined above, we hypothesised that chronic supplementation with creatine monohydrate would be associated with improvement in depressive symptoms and in cognitive measures when used as an adjunctive treatment for bipolar depression in a 6-week, randomized, double-blind, placebo-controlled, proof-of-concept clinical trial.