The neurobiological bases of mood instability are poorly understood. Neuronal network alterations and neurometabolic abnormalities have been implicated in the pathophysiology of mood and anxiety conditions associated with mood instability and hence are candidate mechanisms underlying its neurobiology. Fast-spiking parvalbumin GABAergic interneurons modulate the activity of principal excitatory neurons through their inhibitory action determining precise neuronal excitation balance. These interneurons are directly involved in generating neuronal networks activities responsible for sustaining higher cerebral functions and are especially vulnerable to metabolic stress associated with deficiency of energy substrates or mitochondrial dysfunction. Parvalbumin interneurons are therefore candidate key players involved in mechanisms underlying the pathogenesis of brain disorders associated with both neuronal networks’ dysfunction and brain metabolism dysregulation. To provide empirical support to this hypothesis, we hereby report meta-analytical evidence of parvalbumin interneurons loss or dysfunction in the brain of patients with Bipolar Affective Disorder (BPAD), a condition primarily characterized by mood instability for which the pathophysiological role of mitochondrial dysfunction has recently emerged as critically important. We then present a comprehensive review of evidence from the literature illustrating the bidirectional relationship between deficiency in mitochondrial-dependent energy production and parvalbumin interneuron abnormalities. We propose a mechanistic explanation of how alterations in neuronal excitability, resulting from parvalbumin interneurons loss or dysfunction, might manifest clinically as mood instability, a poorly understood clinical phenotype typical of the most severe forms of affective disorders. The evidence we report provides insights on the broader therapeutic potential of pharmacologically targeting parvalbumin interneurons in psychiatric and neurological conditions characterized by both neurometabolic and neuroexcitability abnormalities.

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AimsTo summarise the tolerability profile following an infusion of methylene blue (MB), including subjective effects on mood and energy levels and haemodynamic changes, in patients with Bipolar Affective Disorder (BPAD).BackgroundBPAD is associated with mitochondrial dysfunction and impaired cellular energy production. MB is proposed to enhance mitochondria function via rerouting electrons and intracellular reduction of oxidative stress, and is therefore a candidate compound for use as a probe to reveal alterations in brain oxygen metabolism in vivo in patients with BPAD. Although there are reports of MB used as treatment for BPAD, the tolerability and subjective effects of a single IV dose in this population has not yet been defined.MethodUsing a single-blind, randomised, within-subject design, 7 patients with BPAD on stable pharmacological treatment and 6 healthy controls (HCs) received an infusion of 0.5mg/kg MB and a placebo glucose solution one week apart. Visual Analogue Scales (VAS) assessing ‘Mood’ and ‘Energy’ levels were completed by 11 participants, and blood pressure (BP), heart rate (HR) and any subsequent side effects were recorded before and after infusions.ResultA significant, albeit very small, effect of MB on ‘Mood’ levels relative to placebo was demonstrated, independent of groups (change relative to baseline: 5.5% ± 11 increase (placebo) vs -1.6 % ± 9.5 reduction (MB); p = 0.027). Although there was no effect of MB on energy levels in either group, there appeared to be a trend for a general group difference in ‘Energy’ levels across all trials, with lower ratings in BPAD patients (p = 0.058).There was a trend for significantly lower post-infusion HR relative to pre-infusion (-6.4 ± 8.8 bpm, p = 0.07. Diastolic BP was higher (3.0 ± 7.8mmHg, p = 0.039). These effects were independent of groups and drug. The most common side effect with MB was mild/moderate pain at infusion site (n = 10/13), resolving within median 32.5 minutes (IQR 6-102), and discoloured urine in 7/13 subjects lasting median 44.5 hours (IQR 36-59). No difference in frequency of side effects reported between groups.ConclusionAlthough limited by small sample size, this tolerability analysis demonstrates a acceptable profile of effects of MB on subjective ratings and blood pressure, in both BPAD and HCs. Common side effects of discoloured urine and pain at infusion site are in line with previous reports in the literature. We observed a small effect of MB on mood ratings which could be related to the discomfort experienced during infusion.