Shan H. Siddiqi

The human experience with intravenous levodopa

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 (IV) 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 IV levodopa were examined for details of administration, pharmacokinetics, benefit, and side effects. Results: We identified 142 original reports describing IVLD use in humans, beginning with psychiatric research in 1959–1960 before the development of peripheral decarboxylase inhibitors. At least 2760 subjects have received IV levodopa, and reported outcomes include parkinsonian signs, sleep variables, hormone levels, 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 Parkinsons 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 2760 patients have received IV levodopa with a safety profile comparable to that seen with oral administration.

Use of the Temperament and Character Inventory to predict response to repetitive transcranial magnetic stimulation for major depression

Objective: The goal of this study was to investigate the utility of the Temperament and Character Inventory (TCI) in predicting antidepressant response to repetitive transcranial magnetic stimulation (rTMS). Background: Although rTMS of the dorsolateral prefrontal cortex 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 pharmacotherapy and cognitive-behavioral therapy. A previous study suggested a possible association between self-directedness and response to rTMS in melancholic depression, although this was limited by the fact that melancholic depression is associated with a limited range of TCI profiles. Methods: Nineteen patients with a major depressive episode completed the TCI before a clinical course of rTMS over the dorsolateral prefrontal cortex. Treatment response was defined as ≥50% decrease in scores on the Hamilton Rating Scale for Depression (Ham-D). Baseline scores on each TCI dimension were compared between responders and nonresponders through analysis of variance. Pearson correlations were also calculated for temperament/character scores in comparison with percentage improvement in Ham-D scores. Results: Eleven of the 19 patients responded to rTMS. T-scores for persistence were significantly higher in responders than in nonresponders (P=0.022). Linear regression revealed a correlation between persistence scores and percentage improvement in Ham-D scores. Conclusions: Higher persistence scores 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.

Orthostatic stability with intravenous levodopa

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.

rTMS with individualized resting-state network mapping for neuropsychiatric sequelae of repetitive traumatic brain injury in a retired NFL player

The recent advent of individualized resting-state network mapping (RSNM) has revealed substantial inter-individual variability in anatomical localization of brain networks identified using resting-state functional MRI (rsfMRI). Such variability may be particularly important after repetitive traumatic brain injury (TBI), which is associated with treatment-resistant depression. RSNM enables personalized targeting of repetitive transcranial magnetic stimulation (rTMS), a focal brain stimulation technique that relieves depression when administered over dorsolateral prefrontal cortex. RSNM was used to identify left/right dorsolateral prefrontal rTMS targets with maximal difference between dorsal attention network and default mode network (DMN) correlations. These targets were spatially distinct from those identified by prior methods. The method was evaluated by administering twenty sessions of left-sided excitatory and right-sided inhibitory rTMS to a retired NFL defensive lineman with progressive treatment-resistant neuropsychiatric disturbances. Treatment led to improvement in Montgomery-Asberg Depression Rating Scale (72%), cognitive testing, and headache scales. In comparison with healthy individuals and subjects with TBI-associated depression, baseline rsfMRI revealed substantially elevated DMN connectivity with medial temporal lobe (MTL). Serial rsfMRI scans showed gradual improvement in MTL-DMN connectivity and stimulation site connectivity with subgenual anterior cingulate cortex. This highlights the possibility of individualized neuromodulation and biomarker-based monitoring for neuropsychiatric sequelae of repetitive TBI.Objective: To investigate clinical utility and brain network changes following resting-state functional MRI (rsfMRI)-targeted bilateral repetitive transcranial magnetic stimulation (rTMS) in a subject with neuropsychiatric disturbances associated with chronic/repetitive traumatic brain injury (TBI). Methods: Individual-level connectome mapping was used to identify left/right dorsolateral prefrontal targets with maximum anticorrelation between dorsal attention network (DAN) and default mode network (DMN). Twenty sessions of left-sided excitatory and right-sided inhibitory rTMS were delivered to a retired NFL defensive lineman as part of a randomized, controlled trial. Montgomery-Asberg Depression Rating Scale (MADRS), cognitive testing, headache measures, and rsfMRI were conducted before and after treatment. Pre-treatment rsfMRI findings were compared to 12 age/gender-matched healthy individuals and 10 subjects with depression and TBI. Results: MADRS score improved from 32 at baseline to 9 immediately after treatment and remained at 9 upon six-week follow-up. Cognitive/headache measures showed mild improvements and treatments were well-tolerated. In comparison with both comparator groups, baseline rsfMRI revealed near-absence of the typical DAN-DMN anticorrelation and differences in limbic functional connectivity with nucleus accumbens (NAcc). These differences in limbic-NAcc connectivity were attenuated with treatment. The identified left- and right-sided rTMS targets were, respectively, 36/30 mm away from traditional clinical targets for major depression and 10-18/7-8 mm away from targets identified by previously-described imaging-based targeting methods. Conclusions: rsfMRI-targeted rTMS may be a promising treatment for neuropsychiatric sequelae of repetitive TBI. Future research will aim to verify this observation, directly compare targeting methods, and better characterize the distinctions between single and repetitive TBI.