BACKGROUND AND THEORY The use of non-invasive brain stimulation for the treatment of various neuropsychiatric disorders, including major depressive disorder (MDD), has rapidly expanded recently. Transcranial direct current electrical stimulation (tDCS), variants of which have been used experimentally for psychiatric , neurologic , and physical rehabilitation applications, has garnered a great deal of attention. While it is not yet FDA-approved for any indication, its promise is related to its low cost and wide range of applications; although the breadth of its applicability has been questioned due to heterogeneous data , this heterogeneity has been attributed to methodological variability . The safety and tolerability of tDCS were outlined by an early study including 567 sessions in 102 patients. The most common adverse effects were mild tingling/itching at the stimulation site and moderate fatigue. Less frequent effects included headaches (11.8%), nausea (2.9%), and insomnia (0.98%), all of which were mild and transient . The underlying theory is that tDCS modulates the excitability of certain cortical regions by passage of a small electrical current through conducting pads applied to the scalp in a minimally painful manner. While the precise mechanism is not fully understood, it likely enhances cortical excitability at the anode and depresses it at the cathode . Proposed mechanisms have been based on data demonstrating relationships between tDCS stimulation and neuropharmacologic effects, cortical electrophysiology, and functional neuroimaging changes. Effects of tDCS on neuroplasticity and cortical excitability have been shown to be differentially modulated by agents affecting neurotransmission via serotonin (citalopram), dopamine (L-dopa), NMDA (dextromethorphan and d-cycloserine), and GABA (lorazepam). Electrophysiologic changes include differential modulation in the presence of agents that modulate sodium channels (carbamazepine) and calcium channels (flunarizine) . Active tDCS shows significant increases in prefrontal cortex activity as measured by functional near infrared spectroscopy (fNIRS), a technique used to measure cortical oxygenation, during and after stimulation – notably, fNIRS measurements may be limited by interference due extracranial blood flow and inability to assess deeper structures, so they merely approximate the functional magnetic resonance imaging (fMRI) signal in superficial structures . Stimulation also increases fMRI activation and connectivity of the underlying cortical regions and hippocampi, though the clinical significance of this is uncertain given that this same study found no behavioral changes .

ABSTRACT OBJECTIVE: We investigated the utility of the Temperament and Character Inventory (TCI) in predicting antidepressant response to rTMS. BACKGROUND: Although rTMS of the dorsolateral prefrontal cortex (DLPFC) is an established antidepressant treatment, little is known about predictors of response. The TCI measures multiple personality dimensions (harm avoidance, novelty seeking, reward dependence, persistence, self-directedness, self-transcendence, and cooperativeness), some of which have predicted response to antidepressants and cognitive-behavioral therapy. A previous study suggested a possible association between higher self-directedness and rTMS response specifically in melancholic depression, although this was limited by the fact that melancholic depression is associated with a limited range of TCI profiles. METHODS: Sixteen patients in a major depressive episode completed a TCI prior to a clinical course of rTMS over the DLPFC. Treatment response was defined as ≥50% decrease in Hamilton Depression Rating Scale (HDRS). Baseline scores on each TCI dimension were compared between responders and non-responders via paired t-test with Bonferroni correction. Temperament/character scores were also subjected to regression analysis against percentage improvement in HDRS. RESULTS: Ten of the sixteen patients responded to rTMS. T-scores for Persistence were significantly higher in responders (48.3, 95% CI 40.9-55.7) than in non-responders (35.3, 95% CI 29.2-39.9) (p=0.006). Linear regression revealed a correlation between persistence score and percentage improvement in HRDS (R=0.65±0.29). CONCLUSIONS: Higher persistence predicted antidepressant response to rTMS. This may be explained by rTMS-induced enhancement of cortical excitability, which has been found to be decreased in patients with high persistence. Personality assessment that includes measurement of TCI persistence may be a useful component of precision medicine initiatives in rTMS for depression.

ABSTRACT OBJECTIVE: To compile a comprehensive summary of published human experience with levodopa given intravenously, with a focus on information required by regulatory agencies. BACKGROUND: While safe intravenous use of levodopa has been documented for over 50 years, regulatory supervision for pharmaceuticals given by a route other than that approved by the U.S. Food and Drug Administration (FDA) has become increasingly cautious. If delivering a drug by an alternate route raises the risk of adverse events, an investigational new drug (IND) application is required, including a comprehensive review of toxicity data. METHODS: Over 200 articles referring to intravenous levodopa (IVLD) were examined for details of administration, pharmacokinetics, benefit and side effects. RESULTS: We identified 144 original reports describing IVLD use in humans, beginning with psychiatric research in 1959-1960 before the development of peripheral decarboxylase inhibitors. At least 2781 subjects have received IVLD, and reported outcomes include parkinsonian signs, sleep variables, hormones, hemodynamics, CSF amino acid composition, regional cerebral blood flow, cognition, perception and complex behavior. Mean pharmacokinetic variables were summarized for 49 healthy subjects and 190 with Parkinson disease. Side effects were those expected from clinical experience with oral levodopa and dopamine agonists. No articles reported deaths or induction of psychosis. CONCLUSION: At least 2781 patients have received i.v. levodopa with a safety profile comparable to that seen with oral administration.

Intravenous levodopa has been used in a multitude of research studies due to its more predictable pharmacokinetics compared to the oral form, which is used frequently as a treatment for Parkinson’s disease (PD). Levodopa is the precursor for dopamine, and intravenous dopamine would strongly affect vascular tone, but peripheral decarboxylase inhibitors are intended to block such effects. Pulse and blood pressure, with orthostatic changes, were recorded before and after intravenous levodopa or placebo—after oral carbidopa—in 13 adults with a chronic tic disorder and 16 tic-free adult control subjects. Levodopa caused no statistically or clinically significant changes in blood pressure or pulse. These data add to previous data that support the safety of i.v. levodopa when given with adequate peripheral inhibition of DOPA decarboxylase.