Edward C. Lauterbach

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

ObjectiveTo 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. BackgroundWe previously identified increases in Diagnostic and Statistical Manual of Mental Disorders, third edition generalized anxiety in dystonia and panic attacks in Parkinson disease. MethodStructured Clinical Interview (SCID) ascertainment of Diagnostic and Statistical Manual of Mental Disorders, third edition, revised, disorders. ResultsGeneralized 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. ConclusionsThese findings suggest relations of generalized anxiety with reduced pallidal inhibition of thalamofrontotemporal projections, and panic attacks with locus coeruleus dysfunction.

Melatonin in antinociception: its therapeutic applications.

The intensity of pain sensation exhibits marked day and night variations. Since the intensity of pain perception is low during dark hours of the night when melatonin levels are high, this hormone has been implicated as one of the prime antinociceptive substances. A number of studies have examined the antinociceptive role of melatonin in acute, inflammatory and neuropathic pain animal models. It has been demonstrated that melatonin exerts antinociceptive actions by acting at both spinal cord and supraspinal levels. The mechanism of antinociceptive actions of melatonin involves opioid, benzodiazepine, α1- and α2-adrenergic, serotonergic and cholinergic receptors. Most importantly however, the involvement of MT1/MT2 melatonergic receptors in the spinal cord has been well documented as an antinociceptive mechanism in a number of animal models of pain perception. Exogenous melatonin has been used effectively in the management of pain in medical conditions such as fibromyalgia, irritable bowel syndrome and migraine and cluster headache. Melatonin has been tried during surgical operating conditions and has been shown to enhance both preoperative and post-operative analgesia. The present review discusses the available evidence indicating that melatonin, acting through MT1/MT2 melatonin receptors, plays an important role in the pathophysiological mechanism of pain.

Bipolar disorders, dystonia, and compulsion after dysfunction of the cerebellum, dentatorubrothalamic tract, and substantia nigra

Bipolar disorders occurred in 3 of 15 (20%) subjects after focal cerebellar circuit lesions. Two presented with rapid cycling bipolar disorder and dystonia, including one with a checking compulsion. Lesions included right cerebellar hypoplasia (bipolar disorder), bilateral cerebellar atrophy (rapid cycling unipolar mania and dystonia), and left midbrain pathology (mixed bipolar disorder, dystonia, and compulsion). Bipolar disorders were associated with cerebellar circuit pathology (p = 0.032) and were more prevalent than in population controls (p = 0.004). Diminished cerebellar output (to cortical, thalamic, basal ganglia, limbic, or other circuits) or nigral pars reticulata dysfunction may result in abnormal neuronal oscillation in bipolar disorders, especially rapid-cycling types, or in dystonia. Review of the literature supports the concept of nigral and cerebellar direct and indirect connections with thalamofrontotemporal and basal ganglia circuits in bipolar disorders, dystonia, and compulsions, as well as possible clinical relationships between these disorders.

Dextromethorphan as a potential rapid-acting antidepressant

Dextromethorphan shares pharmacological properties in common with antidepressants and, in particular, ketamine, a drug with demonstrated rapid-acting antidepressant activity. Pharmacodynamic similarities include actions on NMDA, μ opiate, sigma-1, calcium channel, serotonin transporter, and muscarinic sites. Additional unique properties potentially contributory to an antidepressant effect include actions at ß, alpha-2, and serotonin 1b/d receptors. It is therefore, hypothesized that dextromethorphan may have antidepressant efficacy in bipolar, unipolar, major depression, psychotic, and treatment-resistant depressive disorders, and may display rapid-onset of antidepressant response. An antidepressant response may be associated with a positive family history of alcoholism, prediction of ketamine response, increased AMPA-to-NMDA receptor activity ratio, antidepressant properties in animal models of depression, reward system activation, enhanced erythrocyte magnesium concentration, and correlation with frontal μ receptor binding potential. Clinical trials of dextromethorphan in depressive disorders, especially treatment-resistant depression, now seem warranted.

Toward a more precise, clinically—informed pathophysiology of pathological laughing and crying

Involuntary emotional expression disorder (IEED) includes the syndromes of pathological laughing and crying (PLC) and emotional lability (EL). Review of the lesion, epilepsy, and brain stimulation literature leads to an updated pathophysiology of IEED. A volitional system involving frontoparietal (primary motor, premotor, supplementary motor, posterior insular, dorsal anterior cingulate gyrus (ACG), primary sensory and related parietal) corticopontine projections inhibits an emotionally-controlled system involving frontotemporal (orbitofrontal, ventral ACG, anterior insular, inferior temporal, and parahippocampal) projections targeting the amygdala-hypothalamus-periaqueductal gray (PAG)-dorsal tegmentum (dTg) complex that regulates emotional displays. PAG activity is regulated by glutamatergic NMDA, muscarinic M1-3, GABA-A, dopamine D2, norepinephrine alpha-1,2, serotonin 5HT1a, 5HT1b/d, and sigma-1 receptors, with an acetylcholine/GABA balance mediating volitional inhibition of the PAG. Lesions of the volitional corticopontine projections (or of their feedback or processing circuits) can produce PLC. Direct activation of the emotional pathway can result in EL and the laughing or crying of gelastic and dacrystic epilepsy. A criterion-based nosology of PLC and EL subtypes is offered.

The Differential Diagnosis of Pseudobulbar Affect (PBA): Distinguishing PBA Among Disorders of Mood and Affect

This monograph summarizes the proceedings of a roundtable meeting convened to discuss pseudobulbar affect (PBA). Two didactic lectures were presented followed by a moderated discussion among 11 participants. Post-meeting manuscript development synthesized didactic- and discussion-based content ad incorporated additional material from the neuroscience literature. A conceptual framework with which to distinguish between disorders of mood and affect is presented first, and disorders of affect regulation are then reviewed briefly. A detailed description of the most common of these disorders, PBA, is the focus of the remainder of the monograph. The prevalence, putative neuranatomic and neurochemical bases of PBA are reviewed, and current and emerging methods of evaluation and treatment of persons with PBA are discussed. The material presented in this monograph will help clinicians better recognize, diagnose, and treat PBA, and will form a foundation for understanding and interpreting future studies of this condition.

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. Clinical studies undertaken on patients with major depression, bipolar disorders, seasonal affective disorder, and generalized anxiety disorder have all shown that agomelatine is also very effective in ameliorating depressive symptoms and manifesting early onset of action with a good tolerability and safety profile. It improved sleep efficiency and also resynchronized the disrupted circadian rhythms. Hence, the melatonergic modulation by agomelatine is suggested as one of the mechanisms for its antidepressant effect. Agomelatines action on dendritic neurogenesis in animal models of depression is also identified as yet another action.

An extension of hypotheses regarding rapid-acting, treatment-refractory, and conventional antidepressant activity of dextromethorphan and dextrorphan

It was previously hypothesized that dextromethorphan (DM) and dextrorphan (DX) may possess antidepressant properties, including rapid and conventional onsets of action and utility in treatment-refractory depression, based on pharmacodynamic similarities to ketamine. These similarities included sigma-1 (σ(1)) agonist and NMDA antagonist properties, calcium channel blockade, muscarinic binding, serotonin transporter (5HTT) inhibition, and μ receptor potentiation. Here, six specific hypotheses are developed in light of additional mechanisms and evidence. Comparable potencies to ketamine for DM and DX are detailed for σ(1) (DX>DM>ketamine), NMDA PCP site (DX>ketamine>DM), and muscarinic (DX>ketamine>>>>DM) receptors, 5HTT (DM>DX≫ketamine), and NMDA antagonist potentiation of μ receptor stimulation (DM>ketamine). Rapid acting antidepressant properties of DM include NMDA high-affinity site, NMDR-2A, and functional NMDR-2B receptor antagonism, σ(1) stimulation, putative mTOR activation (by σ(1) stimulation, μ potentiation, and 5HTT inhibition), putative AMPA receptor trafficking (by mTOR activation, PCP antagonism, σ(1) stimulation, μ potentiation, and 5HTT inhibition), and dendritogenesis, spinogenesis, synaptogenesis, and neuronal survival by NMDA antagonism and σ(1) and mTOR signaling. Those for dextrorphan include NMDA high-affinity site and NMDR-2A antagonism, σ(1) stimulation, putative mTOR activation (by σ(1) stimulation and ß adrenoreceptor stimulation), putative AMPA receptor trafficking (by mTOR activation, PCP antagonism, σ(1) stimulation, ß stimulation, and μ antagonism), and dendritogenesis, spinogenesis, synaptogenesis, and neuronal survival by NMDA antagonism and σ(1) and mTOR signaling. Conventional antidepressant properties for dextromethorphan and dextrorphan include 5HTT and norepinephrine transporter inhibition, σ(1) stimulation, NMDA and PCP antagonism, and possible serotonin 5HT1b/d receptor stimulation. Additional properties for dextromethorphan include possible presynaptic α(2) adrenoreceptor antagonism or postsynaptic α(2) stimulation and, for dextrorphan, ß stimulation and possible muscarinic and μ antagonism. Treatment-refractory depression properties include increased serotonin and norepinephrine availability, PCP, NMDR-2B, presynaptic alpha-2 antagonism, and the multiplicity of other antidepressant receptor mechanisms. Suggestions for clinical trials are provided for oral high-dose dextromethorphan and Nuedexta (dextromethorphan combined with quinidine to block metabolism to dextrorphan, thereby increasing dextromethorphan plasma concentrations). Suggestions include exclusionary criteria, oral dosing, observation periods, dose-response approaches, and safety and tolerability are considered. Although oral dextromethorphan may be somewhat more likely to show efficacy through complementary antidepressant mechanisms of dextrorphan, a clinical trial will be more logistically complex than one of Nuedexta due to high doses and plasma level variability. Clinical trials may increase our therapeutic armamentarium and our pharmacological understanding of treatment-refractory depression and antidepressant onset of action.

Neuropsychiatric disorders, myoclonus, and dystonia in calcification of basal ganglia pathways

Two cases of basal ganglia calcification involving the globus pallidus are presented. Both patients had cognitive dysfunction, temporal lobe-like symptoms (including amnestic state, perceptual distortions, or complex visual hallucinations), and myoclonus. Patient 1 manifested depression, auditory hallucinations, anxiety, paranoia, and postural tremor; patient 2 manifested multifocal dystonia with dystonic tremor. These cases supplement other reports of psychotic features and dementia associated with pallidal pathology. Additionally, the phenomena encountered in these cases are considered in light of recent advances in our understanding of basal ganglia functional pathways. These cases afford a potential pathophysiological window to the possible role of the globus pallidus in these neuropsychiatric conditions. In concert with other recent findings, these cases suggest specific pathway involvement in hallucinations, paranoia, depression, myoclonus, and dystonia. Further research will indicate if these pathways play a role in schizophrenia, mood disorders, and anxiety disorders.

Serotonin responsive and nonresponsive diurnal depressive mooddisorders and pathological affect in thalamic infarct associated with myoclonus and blepharospasm

A patient with a central thalamic infarct developed several affective and anxiety disorders that respond differentially to serotoninergic and nonserotoninergic antidepressants. This case, compatible with recent positron emission tomography (PET) data, offers a clinical window to the pathophysiology of mood dysregulation