Early postoperative outcomes of sinus laser closure versus crystallized phenol treatment for pilonidal sinus disease: a retrospective comparative study.

Nearly 40% of individuals with bipolar disorder (BD) develop alcohol use disorder (AUD) over their lifetime []. Co-occurring AUD worsens the course of BD via more frequent and severe manic and depressive episodes, increased resistance to treatment, and increased risk for hospitalization and suicide [, ]. Nonetheless, treatment research for co-occurring BD and AUD (BD + AUD) remains limited, with only seven double-blind, placebo-controlled studies of medications for BD + AUD published to date []. The few randomized controlled trials (RCTs) that have been conducted in people with BD + AUD have evaluated medications FDA approved to treat either BD or AUD in hopes that such medications would prove efficacious for BD + AUD. Unfortunately, under this paradigm, only one, nearly 20-year-old study has demonstrated a positive treatment (i.e., valproate) effect on drinking [] to date. A different approach to developing medications for RCTs would be to target neurobiological dysfunctions characteristic of individuals with BD and/or AUD []. Convergent lines of evidence support dysregulation in prefrontal glutamate and γ-Aminobutyric acid (GABA), the main excitatory and inhibitory neurotransmitters [, ], respectively, as candidate targets for pharmacological intervention in BD + AUD. Impairments in excitatory-inhibitory (E-I) synaptic development and function, biasing E-I synaptic balance towards more excitation, have been consistently found across animal models of mania [], with a recent systematic review of postmortem studies of individuals with BD concordantly reporting robust evidence for decreased cortical GABAergic interneuron density []. Additional molecular evidence of hyper-excitatory E-I dysfunction in BD is provided by studies linking BD with genes coding for glutamate transporters [] and ionotropic and metabotropic receptor subunits [–], reduced expression of GABA receptor subunits and regulating proteins [, ], and differences in GABA receptor genes [–]. H-MRS studies provide a unique opportunity to better understand these issues in humans and have generally demonstrated elevated frontal glutamate + glutamine (Glx) [, ] and GABA [] levels in people with BD relative to healthy control (HC) participants. With respect to AUD, chronic alcohol drinking produces compensatory downregulation of GABA receptors and upregulation of N-methyl-D-aspartate (NMDA) receptors, culminating in the hyper-excitatory state of alcohol withdrawal [, ]. These and related E-I adaptations are believed to be largely responsible for craving, compulsive use, and risk of relapse in individuals with AUD [, ]. In human H-MRS studies, AUD is generally associated with reduced frontal Glx levels in recently drinking individuals [–], with Glx levels transiently elevated during acute alcohol withdrawal []. The cumulative impact of BD- and AUD-related E-I dysfunctions in people with BD + AUD remains minimally studied. In one early H-MRS study, participants with BD + AUD reporting ≥6-months abstinence from alcohol had abnormally low Glx levels in left dorsolateral prefrontal cortex []. We demonstrated that, following ≥7 days of monitored abstinence, individuals with co-occurring BD and current (i.e., within the past 3-months) AUD had significantly lower dorsal ACC (dACC) GABA and glutamate levels [], relative to individuals with BD alone, AUD alone, or HC participants; these deficits were, in turn, significantly associated with higher levels of self-reported alcohol craving and impulsivity. Although no studies to date have investigated effects of medications on brain glutamate or GABA levels in people with BD + AUD, H-MRS studies in other populations have identified safe and well-tolerated medications that reliably alter brain glutamate and/or GABA levels, including gabapentin and n-acetylcysteine (NAC). Gabapentin modulates GABA and glutamate transmission via selective blockade of presynaptic voltage-gated calcium channels that contain the α2δ-1 subunit [] as well as additional E-I-related mechanisms [, ]. In H-MRS studies, both acute [–] and chronic [, ] gabapentin dosing significantly increased occipital GABA levels in healthy volunteers and people with epilepsy in a dose-dependent manner. Though RCTs in treatment-refractory individuals with BD have failed to support the efficacy of gabapentin for resolving acute mood episodes, gabapentin has been shown in some studies to reduce alcohol withdrawal symptoms and relapse drinking in people with AUD [–], in part by modulating frontal glutamate levels [], making it a potentially useful adjunctive treatment strategy for BD + AUD. NAC increases levels of the brain’s primary antioxidant, glutathione, by providing cells with its rate-limiting component, cysteine [], via System x, which imports oxidized cysteine in exchange for glutamate [], thereby activating presynaptic mGlu2 receptors and inhibiting further presynaptic glutamate release []. These glutamatergic effects, manifested in vivo as NAC-induced