An update on adjunctive treatment options for bipolar disorder.

OBJECTIVES: Bipolar disorder is a complex illness often requiring combinations of therapies to successfully treat symptoms. In recent years, there have been significant advancements in a number of therapies for bipolar disorder. It is therefore timely to provide an overview of current adjunctive therapeutic options to help treating clinicians to inform their patients and work towards optimal outcomes. METHODS: Publications were identified from PubMed searches on bipolar disorder and pharmacotherapy, nutraceuticals, hormone therapy, psychoeducation, interpersonal and social rhythm therapy, cognitive remediation, mindfulness, e-Health and brain stimulation techniques. Relevant articles in these areas were selected for further review. This paper provides a narrative review of adjunctive treatment options and is not a systematic review of the literature. RESULTS: A number of pharmacotherapeutic, psychological and neuromodulation treatment options are available. These have varying efficacy but all have shown benefit to people with bipolar disorder. Due to the complex nature of treating the disorder, combination treatments are often required. Adjunctive treatments to traditional pharmacological and psychological therapies are proving useful in closing the gap between initial symptom remission and full functional recovery. CONCLUSIONS: Given that response to monotherapy is often inadequate, combination regimens for bipolar disorder are typical. Correspondingly, psychiatric research is working towards a better understanding of the disorder's underlying biology. Therefore, treatment options are changing and adjunctive therapies are being increasingly recognized as providing significant tools to improve patient outcomes. Towards this end, this paper provides an overview of novel treatments that may improve clinical outcomes for people with bipolar disorder.

The effect of stimulus strength on binocular rivalry rate in healthy individuals: Implications for genetic, clinical and individual differences studies.

Binocular rivalry (BR) occurs when conflicting images concurrently presented to corresponding retinal locations of each eye stochastically alternate in perception. Anomalies of BR rate have been examined in a range of clinical psychiatric conditions. In particular, slow BR rate has been proposed as an endophenotype for bipolar disorder (BD) to improve power in large-scale genome-wide association studies. Examining the validity of BR rate as a BD endophenotype however requires large-scale datasets (n=1000s to 10,000s), a standardized testing protocol, and optimization of stimulus parameters to maximize separation between BD and healthy groups. Such requirements are indeed relevant to all clinical psychiatric BR studies. Here we address the issue of stimulus optimization by examining the effect of stimulus parameter variation on BR rate and mixed-percept duration (MPD) in healthy individuals. We aimed to identify the stimulus parameters that induced the fastest BR rates with the least MPD. Employing a repeated-measures within-subjects design, 40 healthy adults completed four BR tasks using orthogonally drifting grating stimuli that varied in drift speed and aperture size. Pairwise comparisons were performed to determine modulation of BR rate and MPD by these stimulus parameters, and individual variation of such modulation was also assessed. From amongst the stimulus parameters examined, we found that 8cycles/s drift speed in a 1.5° aperture induced the fastest BR rate without increasing MPD, but that BR rate with this stimulus configuration was not substantially different to BR rate with stimulus parameters we have used in previous studies (i.e., 4cycles/s drift speed in a 1.5° aperture). In addition to contributing to stimulus optimization issues, the findings have implications for Levelt's Proposition IV of binocular rivalry dynamics and individual differences in such dynamics.

Evidence that eye-movement profiles do not explain slow binocular rivalry rate in bipolar disorder: support for a perceptual endophenotype.

OBJECTIVES: Presenting conflicting images simultaneously, one to each eye, produces perceptual alternations known as binocular rivalry (BR). Slow BR rate has been proposed as an endophenotype for bipolar disorder (BD) for use in large-scale genome-wide association studies. However, the trait could conceivably reflect eye movement (EM) dysfunction in BD rather than anomalous perceptual processing per se. To address this question, we examined the relationship between EM profiles and BR rate for various stimulus types in BD and healthy subjects. We also examined differences in EM profiles between these groups. METHODS: Employing a repeated-measures within-subjects design, 20 BD outpatients and 20 age- and sex-matched healthy controls completed EM tasks and separate BR tasks involving a range of stimuli with different drift speeds. The association between each EM measure and BR rate was examined with correlational analyses for all stimulus conditions in both groups. Between-group comparisons were performed to determine any differences in those EM measures. Corresponding Bayesian analyses were also conducted. RESULTS: There were no EM measures that showed a significant relationship with BR rate in either the BD group or the healthy group (P≥7.87×10-3 ), where those EM measures were also significantly different between the BD and healthy groups (P≥1.32 × 10-2 ). These findings were verified with Bayes factors. CONCLUSIONS: The results provide evidence that EM profiles do not explain the slow BR endophenotype for BD, thus indicating that the trait reflects anomalous perceptual processing per se. This perceptual trait can be employed in clinical, genetic, mechanistic and pathophysiological studies.

No Relationship Between Binocular Rivalry Rate and Eye-Movement Profiles in Healthy Individuals: A Bayes Factor Analysis.

Binocular rivalry (BR) is an intriguing phenomenon in which conflicting images are presented, one to each eye, resulting in perceptual alternations between each image. The rate of BR has been proposed as a potential endophenotype for bipolar disorder because (a) it is well established that this highly heritable psychiatric condition is associated with slower BR rate than in controls, and (b) an individual's BR rate is approximately 50% genetically determined. However, eye movements (EMs) could potentially account for the slow BR trait given EM anomalies are observed in psychiatric populations, and there has been report of an association between saccadic rate and BR rate in healthy individuals. Here, we sought to assess the relationship between BR rate and EMs in healthy individuals (N = 40, mean age = 34.4) using separate BR and EM tasks, with the latter measuring saccades during anticipatory, antisaccade, prosaccade, self-paced, free-viewing, and smooth-pursuit tasks. No correlation was found between BR rate and any EM measure for any BR task (p > .01) with substantial evidence favoring this lack of association (BF(01) > 3). This finding is in contrast to previous data and has important implications for using BR rate as an endophenotype. If replicated in clinical psychiatric populations, EM interpretations of the slow BR trait can be excluded.

Dichoptic viewing methods for binocular rivalry research: prospects for large-scale clinical and genetic studies.

Binocular rivalry (BR) is an intriguing phenomenon that occurs when two different images are presented, one to each eye, resulting in alternation or rivalry between the percepts. The phenomenon has been studied for nearly 200 years, with renewed and intensive investigation over recent decades. The rate of perceptual switching has long been known to vary widely between individuals but to be relatively stable within individuals. A recent twin study demonstrated that individual variation in BR rate is under substantial genetic control, a finding that also represented the first report, using a large study, of genetic contribution for any post-retinal visual processing phenomenon. The twin study had been prompted by earlier work showing BR rate was slow in the heritable psychiatric condition, bipolar disorder (BD). Together, these studies suggested that slow BR may represent an endophenotype for BD, and heralded the advent of modern clinical and genetic studies of rivalry. This new focus has coincided with rapid advances in 3D display technology, but despite such progress, specific development of technology for rivalry research has been lacking. This review therefore compares different display methods for BR research across several factors, including viewing parameters, image quality, equipment cost, compatibility with other investigative methods, subject group, and sample size, with a focus on requirements specific to large-scale clinical and genetic studies. It is intended to be a resource for investigators new to BR research, such as clinicians and geneticists, and to stimulate the development of 3D display technology for advancing interdisciplinary studies of rivalry.

Genetic contribution to individual variation in binocular rivalry rate.

Binocular rivalry occurs when conflicting images are presented in corresponding locations of the two eyes. Perception alternates between the images at a rate that is relatively stable within individuals but that varies widely between individuals. The determinants of this variation are unknown. In addition, slow binocular rivalry has been demonstrated in bipolar disorder, a psychiatric condition with high heritability. The present study therefore examined whether there is a genetic contribution to individual variation in binocular rivalry rate. We employed the twin method and studied both monozygotic (MZ) twins (n = 128 pairs) who are genetically identical, and dizygotic (DZ) twins (n = 220 pairs) who share roughly half their genes. MZ and DZ twin correlations for binocular rivalry rate were 0.51 and 0.19, respectively. The best-fitting genetic model showed 52% of the variance in binocular rivalry rate was accounted for by additive genetic factors. In contrast, nonshared environmental influences accounted for 18% of the variance, with the remainder attributed to measurement error. This study therefore demonstrates a substantial genetic contribution to individual variation in binocular rivalry rate. The results support the vigorous pursuit of genetic and molecular studies of binocular rivalry and further characterization of slow binocular rivalry as an endophenotype for bipolar disorder.

The changing face of perceptual rivalry.

Functional brain-imaging studies of house-face binocular rivalry and Rubin's vase-faces illusion have consistently reported face perception-dependent activity in the right fusiform gyrus. Here we use Rubin's illusion and report that activation of the left hemisphere by caloric vestibular stimulation increases the predominance of the faces percept in a substantial number of test subjects. While partially supporting the brain-imaging lateralization reports, our findings also challenge these studies by suggesting that neural mechanisms of Rubin's illusion cannot be limited to extrastriate perception-dependent processing. In accordance with our previously proposed interhemispheric switch model, the present findings support the notion that perceptual rivalry engages high-level cortical structures that mediate unihemispheric attentional selection.

The use of tDCS and CVS as methods of non-invasive brain stimulation.

Transcranial direct current stimulation (tDCS) and caloric vestibular stimulation (CVS) are safe methods for selectively modulating cortical excitability and activation, respectively, which have recently received increased interest regarding possible clinical applications. tDCS involves the application of low currents to the scalp via cathodal and anodal electrodes and has been shown to affect a range of motor, somatosensory, visual, affective and cognitive functions. Therapeutic effects have been demonstrated in clinical trials of tDCS for a variety of conditions including tinnitus, post-stroke motor deficits, fibromyalgia, depression, epilepsy and Parkinson's disease. Its effects can be modulated by combination with pharmacological treatment and it may influence the efficacy of other neurostimulatory techniques such as transcranial magnetic stimulation. CVS involves irrigating the auditory canal with cold water which induces a temperature gradient across the semicircular canals of the vestibular apparatus. This has been shown in functional brain-imaging studies to result in activation in several contralateral cortical and subcortical brain regions. CVS has also been shown to have effects on a wide range of visual and cognitive phenomena, as well as on post-stroke conditions, mania and chronic pain states. Both these techniques have been shown to modulate a range of brain functions, and display potential as clinical treatments. Importantly, they are both inexpensive relative to other brain stimulation techniques such as electroconvulsive therapy (ECT) and transcranial magnetic stimulation (TMS).

Caloric vestibular stimulation reveals discrete neural mechanisms for coherence rivalry and eye rivalry: a meta-rivalry model.

Binocular rivalry is an extraordinary visual phenomenon that has engaged investigators for centuries. Since its first report, there has been vigorous debate over how the brain achieves the perceptual alternations that occur when conflicting images are presented simultaneously, one to each eye. Opposing high-level/stimulus-representation models and low-level/eye-based models have been proposed to explain the phenomenon, recently merging into an amalgam view. Here, we provide evidence that during viewing of Díaz-Caneja stimuli, coherence rivalry -- in which aspects of each eye's presented image are perceptually regrouped into rivalling coherent images -- and eye rivalry operate via discrete neural mechanisms. We demonstrate that high-level brain activation by unilateral caloric vestibular stimulation shifts the predominance of perceived coherent images (coherence rivalry) but not half-field images (eye rivalry). This finding suggests that coherence rivalry (like conventional rivalry according to our previous studies) is mediated by interhemispheric switching at a high level, while eye rivalry is mediated by intrahemispheric mechanisms, most likely at a low level. Based on the present data, we further propose that Díaz-Caneja stimuli induce 'meta-rivalry' whereby the discrete high- and low-level competitive processes themselves rival for visual consciousness.

Studies of caloric vestibular stimulation: implications for the cognitive neurosciences, the clinical neurosciences and neurophilosophy.

OBJECTIVE: Caloric vestibular stimulation (CVS) has traditionally been used as a tool for neurological diagnosis. More recently, however, it has been applied to a range of phenomena within the cognitive neurosciences. Here, we provide an overview of such studies and review our work using CVS to investigate the neural mechanisms of a visual phenomenon - binocular rivalry. We outline the interhemispheric switch model of rivalry supported by this work and its extension to a metarivalry model of interocular-grouping phenomena. In addition, studies showing a slow rate of binocular rivalry in bipolar disorder are discussed, and the relationship between this finding and the interhemispheric switch model is described. We also review the effects of CVS in various clinical contexts, explain how the technique is performed and discuss methodological issues in its application. METHODS: A review of CVS and related literature was conducted. RESULTS: Despite CVS being employed with surprising effect in a wide variety of cognitive and clinical contexts, it has been a largely underutilized brain stimulation method for both exploratory and therapeutic purposes. This is particularly so given that it is well tolerated, safe, inexpensive and easy to administer. CONCLUSION: CVS can be used to investigate various cognitive phenomena including perceptual rivalry, attention and mood, as well as somatosensory representation, belief, hemispheric laterality and pain. The technique can also be used to investigate clinical conditions related to these phenomena and may indeed have therapeutic utility, especially with respect to postlesional disorders, mania, depression and chronic pain states. Furthermore, we propose that based on existing reports of the phenomenological effects of CVS and the brain regions it is known to activate, the technique could be used to investigate and potentially treat a range of other clinical disorders. Finally, the effects of CVS (and its potential effects) on several phenomena of interest to philosophy suggest that it is also likely to become a useful tool in experimental neurophilosophy.