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ABSTRACT: 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.
Neuroscience & Biobehavioral Reviews 03/2013; · 8.65 Impact Factor
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Edward C Lauterbach
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ABSTRACT: Psychotropics are widely prescribed in Alzheimer disease (AD) without regard to their pathobiological effects. Results summarize a comprehensive survey of psychotropic effects on messenger ribonucleic acid (mRNA) expression for 52 genes linked to AD. Pending future investigations, current data indicate that atypical antipsychotics, lithium, and fluoxetine reduce AD risk, whereas other drug classes promote risk. Risk may be attenuated by antipsychotics and lithium (down-regulate TNF), atypical antipsychotics (down-regulate TF), risperidone (down-regulates IL1B), olanzapine (up-regulates TFAM, down-regulates PRNP), fluoxetine (up-regulates CLU, SORCS1, NEDD9, GRN, and ECE1), and lithium coadministered with antipsychotics (down-regulates IL1B). Risk may be enhanced by neuroleptics (up-regulate TF), haloperidol (up-regulates IL1B and PION), olanzapine (down-regulates THRA and PRNP, up-regulates IL1A), and chlorpromazine, imipramine, maprotiline, fluvoxamine, and diazepam (up-regulate IL1B). There were no results for dextromethorphan-plus-quinidine. Fluoxetine effects on CLU, NEDD9, and GRN were statistically robust. Drug effects on specific variants, polymorphisms, genotypes, and other genes (CCR2, TF, and PRNP) are detailed. Translational AD risk applications and their limitations related to specific genes, mutations, variants, polymorphisms, genotypes, brain site, sex, clinical population, AD stage, and other factors are discussed. This report provides an initial summary and framework to understand the potential impact of psychotropic drugs on AD-relevant genes.
Alzheimer disease and associated disorders 03/2011; 26(1):1-7. · 2.88 Impact Factor
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Edward C Lauterbach
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ABSTRACT: 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.
Medical Hypotheses 02/2011; 76(5):717-9. · 1.39 Impact Factor
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ABSTRACT: Neuroprotective therapies for neurodegenerative diseases (NDDs) have proven elusive. The established psychotropic agents commonly used to treat the neuropsychiatric manifestations of NDDs are potential neuroprotective therapies, and neuropsychiatrists and others may benefit from a knowledge of the neuroprotective properties of these medications. This report identifies FDA-approved, first-line psychotropic drugs affecting intracellular mechanisms and meriting disease-modifying clinical trials in NDDs. The authors evaluated evidence for neuroprotection according to 1) preclinical; and 2) clinical criteria. Despite low-to-moderate preclinical evidence scores and scant clinical evidence, the most promising investigative priorities are 1) lithium and paroxetine in Alzheimer's disease (AD); 2) lithium in tauopathies (frontotemporal lobar degeneration [FTLD], FTDP-17); 3) lithium-plus-valproate in AD and amyotrophic lateral sclerosis; 4) pramipexole and valproate in Parkinson's disease; 5) amantadine and buspirone in multiple system atrophy; and 6) antidepressants in Huntington's disease. Preliminary clinical results signal caution regarding olanzapine use in AD and poor tolerability of lithium in progressive supranuclear palsy and corticobasal degeneration. These preliminary findings can lead to further clinical drug trials on the use of these well-known medications, not only for their psychotropic effects, but also for neuroprotection in NDDs.
The Journal of neuropsychiatry and clinical neurosciences 01/2011; 23(3):242-60. · 2.34 Impact Factor
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ABSTRACT: Sequential therapeutic trials for catatonoid frontal signs in clinically-evident frontotemporal dementia (n = 2) revealed differential benefits for lorazepam, amantadine, memantine, pramipexole, aripiprazole, quetiapine, citalopram, and donepezil, although certain signs also worsened. Citalopram and donepezil were poorly tolerated. Ramelteon was without effect. While memantine appeared to improve cognition in case 1, this remains to be established by more reliable neuropsychological testing. Parkinsonism (case 2) responded to pramipexole, but not amantadine or levodopa. Possible relationships of catatonoid signs requiring future confirmation include insufficient GABA-A (multiple signs) and D2 (mutism) and excessive NMDA (immobility, rigidity), D2/D3 (mannerisms, verbal perseveration), and 5HT1a (staring) receptor stimulation. Low-dose lorazepam and quetiapine required close monitoring.
Neurocase 10/2010; 16(5):436-50. · 1.11 Impact Factor
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ABSTRACT: The authors studied mood disorder and neurobehavioral correlates of solitary focal cerebellar (CB) lesions.
CB function has been correlated with cognitive, behavioral, and psychiatric conditions. Systematic study of uncomplicated CB pathology can further our understanding of these correlates.
Magnetic Resonance Images were blindly selected from 20,000 scans for solitary focal CB lesions after excluding other pathology. "Secondary" conditions (developing after lesion onset) were determined using structured clinical interviews (DIS and SCID) for psychiatric diagnoses while blind to MRI findings. Clinical correlates of lesions and a priori hypotheses were examined in 13 participants while controlling for alternative attributions (atrophy, hyperintensities, ventriculomegaly, disability, etc.).
Bipolar disorders after CB lesions were more common than expected in normal populations (OR 28.62, 95% CI 3.51 < - >233.34, P=0.0001), replicating a previous finding. Secondary DSM-III and -IV depressive disorders correlated with posterolateral lesions of the right CB posterior lobe (P=0.0035); severity correlated with lesion size. Other lesion correlates included hypomania (anterolateral left CB posterior lobe), apathy (medial left anterior lobe, anterolateral right posterior lobe), disinhibition and dysexecution (medial left anterior lobe), agitation (central left and anterolateral right posterior lobe), and elation (anterolateral right posterior lobe). Although other structural cerebral and psychosocial variables did not explain the findings, much larger sample sizes will be needed to adequately control for these variables.
Review of the literature reveals support for these findings, suggesting CB control of mood, behavior, and frontal cognition.
Cognitive and behavioral neurology: official journal of the Society for Behavioral and Cognitive Neurology 06/2010; 23(2):63-73. · 1.09 Impact Factor
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The Journal of neuropsychiatry and clinical neurosciences 01/2010; 22(1):123c.e4-123.e4. · 2.34 Impact Factor
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ABSTRACT: This manuscript reviews the preclinical in vitro, ex vivo, and nonhuman in vivo effects of psychopharmacological agents in clinical use on cell physiology with a view toward identifying agents with neuroprotective properties in neurodegenerative disease. These agents are routinely used in the symptomatic treatment of neurodegenerative disease. Each agent is reviewed in terms of its effects on pathogenic proteins, proteasomal function, mitochondrial viability, mitochondrial function and metabolism, mitochondrial permeability transition pore development, cellular viability, and apoptosis. Effects on the metabolism of the neurodegenerative disease pathogenic proteins alpha-synuclein, beta-amyloid, and tau, including tau phosphorylation, are particularly addressed, with application to Alzheimer's and Parkinson's diseases. Limitations of the current data are detailed and predictive criteria for translational clinical neuroprotection are proposed and discussed. Drugs that warrant further study for neuroprotection in neurodegenerative disease include pramipexole, thioridazine, risperidone, olanzapine, quetiapine, lithium, valproate, desipramine, maprotiline, fluoxetine, buspirone, clonazepam, diphenhydramine, and melatonin. Those with multiple neuroprotective mechanisms include pramipexole, thioridazine, olanzapine, quetiapine, lithium, valproate, desipramine, maprotiline, clonazepam, and melatonin. Those best viewed circumspectly in neurodegenerative disease until clinical disease course outcomes data become available, include several antipsychotics, lithium, oxcarbazepine, valproate, several tricyclic antidepressants, certain SSRIs, diazepam, and possibly diphenhydramine. A search for clinical studies of neuroprotection revealed only a single study demonstrating putatively positive results for ropinirole. An agenda for research on potentially neuroprotective agent is provided.
The Journal of neuropsychiatry and clinical neurosciences 01/2010; 22(1):8-18. · 2.34 Impact Factor
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ABSTRACT: In Part I of this report, the authors reviewed preclinical and clinical evidence of neuroprotection by psychotropics and proposed criteria to predict translational neuroprotection. Here, the authors review a broad array of neuroprotective mechanisms and, based on evidence reviewed in Part I, consider agents with pharmacodynamic mechanisms of action that may be associated with neuroprotection. The neuroprotective potential of the pharmacodynamic mechanisms discussed here are held in common with drugs that evidenced neuroprotective potential in Part I. The agents examined here have symptomatic utility in neurodegenerative disease neuropsychiatric disorders and combine the most promising pharmacodynamic mechanisms yet have received insufficient research to date. Modafinil, duloxetine, ziprasidone, s-zopiclone, and ramelteon are evaluated in terms of their putative neuropsychiatric symptomatic and heuristic neuroprotective disease-modifying potentials. The authors review these agents in terms of their potential for clinical neuroprotection and suggest a criterion-based research agenda for future studies of their neuroprotective potential. Further research is needed with regard to the 10 translational neuroprotective candidate criteria, neuroprotective clinical trials, the correlation of psychotropic pharmacodynamic mechanisms with neuroprotective actions, and the translational predictive utility of the proposed candidate criteria.
The Journal of neuropsychiatry and clinical neurosciences 01/2010; 22(2):130-54. · 2.34 Impact Factor
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ABSTRACT: Pathological laughing and crying (PLC) is a clinical condition that occurs in patients with various neurological disorders. It is characterized by the presence of episodic and contextually inappropriate or merely exaggerated outbursts of laughter and/or crying without commensurate feelings. This review provides an in depth analysis of the neuroanatomy of lesions seen in patients with this clinical condition, discusses the relevant functional neuroimaging and electrophysiological stimulation studies in human subjects, and summarizes the current treatment options. It concludes with a presentation of the remaining questions and directions for future research.
The Journal of neuropsychiatry and clinical neurosciences 02/2009; 21(1):75-87. · 2.34 Impact Factor
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ABSTRACT: Several lines of evidence suggest that D-amphetamine (D-AMPH) withdrawal induces a syndrome with symptoms similar to major depressive disorder (MDD). Upregulation of dynorphin (DYN) may underlie the symptoms of MDD and contribute to the negative emotional symptoms associated with psychostimulant withdrawal. Changes in the serotonin transporter (SERT) have also been reported in MDD, and changes in the immediate early gene c-fos have been observed in the context of psychostimulant withdrawal. This study examined the effects of chronic, escalating doses of D-AMPH followed by 24 h of withdrawal on the expression of prodynorphin (PD) and c-fos mRNA in limbic regions of the brain, caudate putamen (CPu), and brainstem and SERT mRNA expression in the dorsal raphe nucleus (DRN). Male Sprague-Dawley rats were treated three times a day for 4 days with escalating doses of D-AMPH (1-10 mg/kg) and sacrificed 24 h after the last injection. Following 24 h of withdrawal, there was an increase in PD and c-fos mRNA expression in the CPu and nucleus accumbens (NAc), and a decrease in PD and c-fos expression in hippocampus and amygdala. SERT mRNA expression was decreased in the DRN, and PD mRNA expression was increased in the adjacent ventrolateral periaqueductal gray (VLPAG) following D-AMPH withdrawal. These data indicate that region-specific changes in PD and c-fos expression occur after withdrawal, while SERT mRNA expression is suppressed, similar to what has been reported in MDD. Alterations in PD, c-fos, and SERT expression could contribute to the depression-like syndrome associated with psychostimulant withdrawal.
Synapse 01/2009; 63(4):257-68. · 2.94 Impact Factor
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ABSTRACT: Urinary incontinence arising in dementia lowers patient quality of life, predicts caregiver burden and nursing home placement, and predisposes to adding additional medicines that can further impair cognition, behavior, and function. An understanding of incontinence pharmacology can help the clinician predict and manage this adverse event in treating patients with dementia.
Case report.
We encountered a patient with Alzheimer's disease and vascular dementia who developed urinary incontinence and parkinsonism when ziprasidone was added to the regimen for behavioral concerns.When he was switched to duloxetine, the incontinence and parkinsonism resolved whereas improvements in perseveration, irritability, paranoia, and agitation persisted.
While a pharmacokinetic explanation is unlikely, the best evidence suggests that ziprasidone-mediated serotonin 5HT2 receptor blockade may explain the reversible incontinence, with an adrenergic alpha-1 receptor mechanism considered to be less likely. Patients on 5HT2 antagonist drugs, including atypical antipsychotics, should be observed for incontinence. In the event of incontinence developing in the context of these agents, duloxetine may represent a potential pharmacological alternative in some cases. Duloxetine may improve neuropsychiatric symptoms in dementia through its effects on serotonin, norepinephrine, and frontal dopamine.
Psychopharmacology bulletin 01/2009; 42(3):99-105. · 1.35 Impact Factor
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ABSTRACT: To report catatonia in neurosyphilis with elevated creatine phosphokinase (CPK) and to understand the pharmacodynamics of catatonia.
Case Report.
We encountered catatonia in a man with neurosyphilis after increasing aripiprazole and valproate (drugs reported to improve catatonia) and reducing doxycycline and temazepam dosages, consistent with identified dopamine D2, serotonin 5HT2, and 5HT1a (aripiprazole), GABA-B (valproate), glutamatergic NMDA (aripiprazole, valproate, doxycycline), and GABA-A (aripiprazole, temazepam) mechanisms of catatonia. CPK was markedly elevated despite the absence of neuroleptic malignant syndrome (NMS) and responded to lorazepam, as did the catatonia.
This appears to be the first case report of catatonia without NMS associated with each of the following: neurosyphilis, aripiprazole, and temazepam withdrawal. This case further adds to the emerging literature of catatonia arising with valproate and atypical antipsychotic co-administration, and of non-NMS catatonia associated with CPK elevations. Plural simultaneously - operant pharmacodynamic mechanisms may explain catatonia of unclear etiology and reconcile a seemingly contradictory literature (e.g., the capacity of certain drugs (e.g., aripiprazole, valproate) to either relieve or precipitate catatonia depending on their pharmacological contexts). Besides reduced D2, 5HT2, and GABA-A and increased 5HT1a, GABA-B, and NMDA receptor stimulation appreciated in the clinical literature, stimulation of adenosine, muscarinic, and H1 histamine receptors may also have promoted catatonia in this case and others, whereas the alpha-2 agonist clonidine has alleviated it. Multiple drugs in this regimen and our current reliance on mechanisms determined primarily in preclinical studies now indicate the need for clinical studies to determine the relative importance of each mechanism in human patients.
Psychopharmacology bulletin 01/2009; 42(4):53-63. · 1.35 Impact Factor
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ABSTRACT: The Committee on Research of the American Neuropsychiatric Association conducted a review of the noncognitive neuropsychiatric manifestations of frontotemporal dementia. The Committee on Research searched reviews and several online databases for all pertinent publications. Single case reports without pathology were excluded, except for psychosis, where single cases made up much of the literature. The strongest evidence supports an association of frontotemporal dementia with the following behaviors: apathy-abulia; disinhibition-impulsivity; loss of insight and self-referential behavior; decreased emotion and empathy; violation of social and moral norms; changes in dietary or eating behavior; and repetitive behaviors. Frontotemporal dementia is less frequently associated with anxiety and mood disorders, which may be a prodrome or risk factor, and rarely presents with delusions or hallucinations. The results of this review highlight the distinct neuropsychiatric manifestations of frontotemporal dementia and the need to reconsider the current diagnostic criteria for this disorder.
Journal of Neuropsychiatry 02/2008; 20(2):130-49. · 2.51 Impact Factor
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ABSTRACT: This report reviews the state of the literature and opportunities for research related to the cognitive correlates of functional status. The prediction of functional capacity on the basis of cognitive test performance is an important aspect of neuropsychological assessment. Moreover, functional impairment or "disability" is an essential part of dementia case finding. Nevertheless, relatively little attention has been given to the empirical study of the specific cognitive correlates of functional outcomes. What literature is available suggests that 1) the variance in functional status that can be specifically attributed to cognition is surprisingly modest; 2) some cognitive domains may be more relevant to functional capacity than others; 3) some measures of executive control function are relatively strong correlates of functional capacities, particularly medical or financial decision-making; and 4) "general" cognitive screening tests are surprisingly strong correlates of functional status. These findings are of particular significance to dementia case finding, epidemiology, and treatment. The extensive literature on functional status has yet to be integrated with the equally extensive literature on cognitive assessment. Better integration of cognitive and functional assessments would offer greater clinical utility. However, psychometric batteries may have to be redesigned to maximize their capacity to capture the variance in functional outcomes.
Journal of Neuropsychiatry 02/2007; 19(3):249-65. · 2.51 Impact Factor
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ABSTRACT: Psychiatric disorders frequently complicate recovery and rehabilitation from traumatic brain injury (TBI). This study reviews the literature from 1978 to 2006 on psychosis, depression, posttraumatic stress disorder, mania, and aggression following nonpenetrating TBI. The studies were reviewed using the American Academy of Neurology's criteria for classification of articles on diagnostic methods. No studies were found to be Class I or II. Of the 66 studies reviewed, the majority were Class IV. There are significant gaps in the literature on post-TBI psychiatric conditions with respect to nosology, epidemiology, and risk factors. Larger multicenter prospective studies using standardized diagnostic instruments are needed to further clarify the nosology, risk factors, and clinical course of these disorders. Specific directions for research are provided.
Journal of Neuropsychiatry 02/2007; 19(2):106-27. · 2.51 Impact Factor
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Edward C Lauterbach
Neurology India 10/2006; 54(3):246-7. · 0.96 Impact Factor
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ABSTRACT: Uncontrollable episodes of emotional expression occur in a variety of neurological conditions. This emotional disinhibition syndrome is characterized by episodes of crying or laughing that are unrelated to or out of proportion to the eliciting stimulus. This syndrome is common among patients with amyotrophic lateral sclerosis, multiple sclerosis, stroke, and traumatic brain injury and a variety of terms and definitions have been used to describe it. The confusing nomenclature has been a barrier to understanding, diagnosis, and treatment of this disorder. The authors propose a unifying term, involuntary emotional expression disorder (IEED), and provide diagnostic criteria for this disorder.
CNS spectrums 07/2006; 11(6):1-7. · 2.20 Impact Factor
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ABSTRACT: The authors evaluate quantitative electroencephalography (qEEG) as a laboratory test in clinical psychiatry and describe specific techniques, including visual analysis, spectral analysis, univariate comparisons to normative healthy databases, multivariate comparisons to normative healthy and clinical databases, and advanced techniques that hold clinical promise. Controversial aspects of each technique are discussed, as are broader areas of criticism, such as commercial interests and standards of evidence. The published literature is selectively reviewed, and qEEG's applicability is assessed for disorders of childhood (learning and attentional disorders), dementia, mood disorders, anxiety, panic, obsessive-compulsive disorder, and schizophrenia. Emphasis is placed primarily on studies that use qEEG to aid in clinical diagnosis, and secondarily on studies that use qEEG to predict medication response or clinical course. Methodological problems are highlighted, the availability of large databases is discussed, and specific recommendations are made for further research and development. As a clinical laboratory test, qEEG's cautious use is recommended in attentional and learning disabilities of childhood, and in mood and dementing disorders of adulthood.
Journal of Neuropsychiatry 02/2006; 18(4):460-500. · 2.51 Impact Factor
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David B Arciniegas, Edward C Lauterbach,
Karen E Anderson,
Tiffany W Chow,
Laura A Flashman,
Robin A Hurley,
Daniel I Kaufer,
Thomas W McAllister,
Alison Reeve,
Randolph B Schiffer,
Jonathan M Silver
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ABSTRACT: 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.
CNS spectrums 06/2005; 10(5):1-14; quiz 15-6. · 2.20 Impact Factor
