The Neuroprotective Disease-Modifying Potential of Psychotropics in Parkinson's Disease

Neuroprotective treatments in Parkinson's disease (PD) have remained elusive. Psychotropics are commonly prescribed in PD without regard to their pathobiological effects. The authors investigated the effects of psychotropics on pathobiological proteins, proteasomal activity, mitochondrial functions, apoptosis, neuroinflammation, trophic factors, stem cells, and neurogenesis. Only findings replicated in at least 2 studies were considered for these actions. Additionally, PD-related gene transcription, animal model, and human neuroprotective clinical trial data were reviewed. Results indicate that, from a PD pathobiology perspective, the safest drugs (i.e., drugs least likely to promote cellular neurodegenerative mechanisms balanced against their likelihood of promoting neuroprotective mechanisms) include pramipexole, valproate, lithium, desipramine, escitalopram, and dextromethorphan. Fluoxetine favorably affects transcription of multiple genes (e.g., MAPT, GBA, CCDC62, HIP1R), although it and desipramine reduced MPTP mouse survival. Haloperidol is best avoided. The most promising neuroprotective investigative priorities will involve disease-modifying trials of the safest agents alone or in combination to capture salutary effects on H3 histone deacetylase, gene transcription, glycogen synthase kinase-3, α-synuclein, reactive oxygen species (ROS), reactive nitrogen species (RNS), apoptosis, inflammation, and trophic factors including GDNF and BDNF

Early psychiatric morbidity in a Brazilian sample of acute ischemic stroke patients

OBJECTIVE: Stroke is a major public health problem worldwide, and its neuropsychiatric sequelae are frequent and disabling. Furthermore, there is evidence that these sequelae impair recovery. Brazil has the highest stroke rates in Latin America, but data on the frequency of neuropsychiatric disorders in these patients are scarce. This study aimed to identify mental disorders among in-hospital patients with acute ischemic stroke. METHODS: The Mini International Neuropsychiatric Interview-Plus (MINI-Plus) was applied to 60 patients during the first week of hospitalization. RESULTS: Psychiatric disorders were diagnosed in 55% of the patients. A wide range of neuropsychiatric disorders have been identified, mainly mood and anxiety disorders. Specifically, we identified major depression (26.7%), alcohol abuse or dependence (11.7%), specific phobia (8.3%), generalized anxiety disorder (6.7%), psychosis (5.0%), social phobia (3.3%), adjustment disorder (3.3%) and panic disorder (1.7%). CONCLUSION: Psychiatric comorbidity should be evaluated as part of the rehabilitation of stroke patients and should be carefully examined by physicians

Agomelatine in Depressive Disorders: Its Novel Mechanisms of Action

Disruptions in sleep and sleep–wake cycle regulation have been identified as one of the main causes for the pathophysiology of depressive disorders. The search has been on for the identification of an ideal antidepressant that could improve both sleep disturbances and depressive symptomatology. Melatonin, the major hormone of the pineal gland, has been shown to improve sleep and is involved in the regulation of the sleep–wake cycle. Identification of high concentrations of MT1 and MT2 melatonergic receptors in the suprachiasmatic nucleus of the anterior hypothalamus, the structure concerned with regulation of circadian rhythms and sleep–wake cycles, has led to the development of melatonergic agonists with greater potency and longer durations of action. Agomelatine is one such melatonergic agonist that acts specifically on MT1/MT2 melatonergic receptors and at the same time exhibits 5-HT2C antagonism, a property that is utilized by current antidepressants that are in clinical use. Agomelatine has been shown to be effective in a number of animal models of depression

Six psychotropics for pre-symptomatic & early Alzheimer's (MCI), Parkinson's, and Huntington's disease modification

The quest for neuroprotective drugs to slow the progression of neurodegenerative diseases (NDDs), including Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD), has been largely unrewarding. Preclinical evidence suggests that repurposing quetiapine, lithium, valproate, fluoxetine, donepezil, and memantine for early and pre-symptomatic disease-modification in NDDs may be promising and can spare regulatory barriers. The literature of these psychotropics in early stage and pre-symptomatic AD, PD, and HD is reviewed and propitious findings follow. Mild cognitive impairment (MCI) phase of AD: salutary human randomized controlled trial findings for low-dose lithium and, in selected patients, donepezil await replication. Pre-symptomatic AD: human epidemiological data indicate that lithium reduces AD risk. Animal model studies (AMS) reveal encouraging results for quetiapine, lithium, donepezil, and memantine. Early PD: valproate AMS findings show promise. Pre-symptomatic PD: lithium and valproate AMS findings are encouraging. Early HD: uncontrolled clinical data indicate non-progression with lithium, fluoxetine, donepezil, and memantine. Pre-symptomatic HD: lithium and valproate are auspicious in AMS. Many other promising findings awaiting replication (valproate in MCI; lithium, valproate, fluoxetine in pre-symptomatic AD; lithium in early PD; lithium, valproate, fluoxetine in pre-symptomatic PD; donepezil in early HD; lithium, fluoxetine, memantine in pre-symptomatic HD) are reviewed. Dose- and stage-dependent effects are considered. Suggestions for signal-enhancement in human trials are provided for each NDD stage

Differential DSM-III Psychiatric Disorder Prevalence Profiles in Dystonia and Parkinson Disease

The authors investigated the prevalence of DIS-ascertained DSM-III psychiatric disorders occurring in 28 patients with dystonia and 28 patients with Parkinson’s Disease (PD). In patients with dystonia, lifetime prevalences of major depression (25.0%), bipolar disorder (7.1%), atypical bipolar disorder (7.1%), social phobia (17.9%), and generalized anxiety disorder (25.0%) were significantly more common than in epidemiologic catchment area (ECA) study population controls (p \u3c 0.005). Social phobia and generalized anxiety disorder preceded dystonia (primary), while bipolar disorder developed after dystonia onset (secondary). In PD patients, the lifetime prevalence of simple phobia (35.7%, p \u3c 0.0001) and atypical depression (21.4%) were significantly more common. Parkinson’s Disease was associated with primary simple phobia and secondary atypical depression. These findings are considered in light of previous results and in terms of the differences in pallidothalamic physiologies in dystonia and PD. These data suggest distinctive profiles of psychiatric disorders in dystonia and PD

Correlates of Generalized Anxiety and Panic Attacks in Dystonia and Parkinson Disease

Objective: To determine prevalences of generalized anxiety, generalized anxiety disorder, panic attacks, and panic disorder in primary dystonia (n = 28) and Parkinson disease (n = 28) and to explore their clinical correlates. Background: We previously identified increases in Diagnostic and Statistical Manual of Mental Disorders, third edition generalized anxiety in dystonia and panic attacks in Parkinson disease. Method: Structured Clinical Interview (SCID) ascertainment of Diagnostic and Statistical Manual of Mental Disorders, third edition, revised, disorders. Results: Generalized anxiety disorder was more common in dystonia while panic disorder was more common in Parkinson disease (P = 0.0018). Generalized anxiety developed more commonly after dystonia onset (i.e., secondary generalized anxiety) while panic attacks developed more commonly after Parkinson disease onset (P = 0.0132). Specific life prevalences were: generalized anxiety disorder, 7 subjects (25.0%) in dystonia versus 0 subjects (0.0%) in Parkinson disease; generalized anxiety, 11 (39.3%) versus 0 (0.0%); panic disorder, 2 (7.1%) versus 7 (25.0%); and panic attacks, 2 (7.1%) versus 9 (32.1%). Exploratory analysis in Parkinson disease indicated a relationship of panic disorder (P = 0.027) and secondary panic attacks (P = 0.0009) to motor block frequency. There were nonsignificant trends toward associations of secondary generalized anxiety with lower Mini Mental Status Examination scores (P = 0.058), and of secondary panic attacks with presence of a depressive disorder (P = 0.077). Depressive comorbidity rates are also presented. Conclusions: These findings suggest relations of generalized anxiety with reduced pallidal inhibition of thalamofrontotemporal projections, and panic attacks with locus coeruleus dysfunction

Dextromethorphan as a potential neuroprotective agent with unique mechanisms of action

BACKGROUND: Dextromethorphan (DM) is a widely-used antitussive. DM\u27s complex central nervous system (CNS) pharmacology became of interest when it was discovered to be neuroprotective due to its low-affinity, uncompetitive N-methyl-d-aspartate (NMDA) receptor antagonism. REVIEW SUMMARY: Mounting preclinical evidence has proven that DM has important neuroprotective properties in various CNS injury models, including focal and global ischemia, seizure, and traumatic brain injury paradigms. Many of these protective actions seem functionally related to its inhibitory effects on glutamate-induced neurotoxicity via NMDA receptor antagonist, sigma-1 receptor agonist, and voltage-gated calcium channel antagonist actions. DM\u27s protection of dopamine neurons in parkinsonian models may be due to inhibition of neurodegenerative inflammatory responses. Clinical findings are limited, with preliminary evidence indicating that DM protects against neuronal damage. Negative findings seem to relate to attainment of inadequate DM brain concentrations. Small studies have shown some promise for treatment of perioperative brain injury, amyotrophic lateral sclerosis, and symptoms of methotrexate neurotoxicity. DM safety/tolerability trials in stroke, neurosurgery, and amyotrophic lateral sclerosis patients demonstrated a favorable safety profile. DM\u27s limited clinical benefit is proposed to be associated with its rapid metabolism to dextrorphan, which restricts its central bioavailability and therapeutic utility. Systemic concentrations of DM can be increased via coadministration of low-dose quinidine (Q), which reversibly inhibits its first-pass elimination. Potential drug interactions with DM/Q are discussed. CONCLUSIONS: Given the compelling preclinical evidence for neuroprotective properties of DM, initial clinical neuroprotective findings, and clinical demonstrations that the DM/Q combination is well tolerated, this strategy may hold promise for the treatment of various acute and degenerative neurologic disorders. © 2007 Lippincott Williams & Wilkins, Inc