Human Psychopharmacology-clinical and Experimental, May 15, 2023
IntroductionDespite frequent recognition of emotional blunting in the published literature, eithe... more IntroductionDespite frequent recognition of emotional blunting in the published literature, either as a primary symptom of depression or as an adverse effect of antidepressants, there is no systematic synthesis on this topic to our knowledge. We undertook this scoping review to assess the prevalence, clinical features, implicated causes and management of emotional blunting, outlining the phenomenological and clinical gaps in research.MethodA systematic search was done until March 15, 2022, to include all original studies (i.e., interventional trials, cohort & cross‐sectional studies, case reports, and case series). All reviewed data were delineated to answer pertinent clinical, phenomenological, and management questions related to the phenomenon of emotional blunting.ResultsA total of 25 original studies were included in our scoping review. Emotional blunting was described as a persistent diminution in both positive and negative feelings in depressed patients, who could subjectively differentiate it from their acute symptoms. However, the literature lacked the distinction between emotional blunting as a primary symptom of depression or an adverse effect of antidepressants. Common clinical strategies to manage antidepressant‐induced emotional blunting included dose reduction or switching to a different antidepressant.ConclusionEmotional blunting was a significant patient‐reported concern with antidepressants. Future research should clarify phenomenological and neurobiological constructs underlying emotional blunting to improve diagnostic and management skills.
Aim: To review genetic biomarkers of agranulocytosis and efficacy with clozapine as a screening t... more Aim: To review genetic biomarkers of agranulocytosis and efficacy with clozapine as a screening tool for the safe and effective use of clozapine. Methods: A PubMed search was performed using PRISMA guidelines for English articles. Separate searches were conducted using “clozapine” AND “agranulocytosis,” and “clozapine” AND (“response” OR efficacy “outcome”) AND “schizophrenia”. Eligible studies reported positive findings with genetic polymorphism(s) associated with clozapine-induced agranulocytosis (CIA) and clozapine’s efficacy. Case reports/series, abstracts, systematic reviews, and meta-analyses were excluded. Negative and genome-wide studies were not formally reviewed but included in the discussion. Results: Twelve out of 572 CIA studies and 32 out of 126 efficacy studies met the eligibility criteria for this review. Most reviewed studies were conducted in small samples of Jewish, Caucasian, and Asian populations using a candidate gene approach. Conclusion: Future research needs to address the limitations of the findings from the reviewed studies to enable a combined genetic screening for CIA and clozapine response to optimize the safe and effective use of clozapine without unnecessarily exposing potential clozapine nonresponders to CIA or neutropenia.
Hyperprolactinemia with low dose of risperidone in a young female To the Editor, Hyperprolactinem... more Hyperprolactinemia with low dose of risperidone in a young female To the Editor, Hyperprolactinemia is a widely recognized adverse effect of antipsychotic medications (APMs). However, most clinicians only monitor extrapyramidal symptoms (EPS) and not prolactin levels, unless adverse effects (AEs), such as sexual dysfunction, are reported. Although most patients treated with average doses of APMs do not develop significant EPS and/or hyperprolactinemia, few patients, especially those with secondary psychosis, can develop these AEs on low doses of APMs. This case discusses how a young Caucasian female with a previous diagnosis of schizophrenia developed significant AEs at a relatively low dose of an APM. History 21 year-old Caucasian female with history of schizophrenia, methamphetamine use, and fetal alcohol syndrome (FAS) was admitted to a state hospital due to worsening psychosis and agitation and continued methamphetamine use. She was being treated with 700 mg a day of quetiapine, which she refused to take due to dizziness and sedation. Patient was willing to be switched to risperidone but despite prolonged cross titration, patient still developed significant akathisia, which resulted in walking for hours and developing blisters on her feet. Patient also reported missing her menstrual periods and her prolactin level was significantly elevated at 135 ng/mL. After ruling out a prolactinoma, risperidone was gradually reduced from 2 mg to 1.5 mg/day and then to 1 mg/day but the level remained elevated at 127 ng/mL and 120 ng/mL, respectively (Table 1) with ongoing akathisia. We decided to gradually discontinue risperidone, within a few days of which, prolactin level normalized with complete resolution of akathisia without any rebound or relapse in psychosis. Discussion Unusual response to a relatively low dose of risperidone with significant EPS, hyperprolactinemia and amenorrhea, led us to
Efforts to improve insight have been ineffective or at best partially effective, which has arouse... more Efforts to improve insight have been ineffective or at best partially effective, which has aroused significant interest to investigate neural substrates for impaired insight in schizophrenia in an effort to develop better treatment strategies. In this context, several studies have revealed an association between impaired insight and deficits in midline and lateral cortical structures (
Patterns of atrophy in frontotemporal dementia (FTD) correlate with the clinical subtypes of beha... more Patterns of atrophy in frontotemporal dementia (FTD) correlate with the clinical subtypes of behavioral variant FTD (bvFTD), semantic dementia, progressive non-fluent aphasia (PNFA) and FTD with motor neuron disease (FTD-MND). Right temporal variant FTD is associated with behavioral dyscontrol and semantic impairment, with tau abnormalities more common in right temporal bvFTD and TDP-43 accumulation in right temporal semantic dementia. However, no clinical and anatomical correlation has been described for patients with predominant right temporal atrophy and FTD-MND. Therefore, we performed a database screen for all patients diagnosed with FTD-MND at Mayo Clinic and reviewed their MRI scans to identify those with striking, dominant, right temporal lobe atrophy. For cases with volumetric MRI we performed voxel based morphometry and for those with brain tissue we performed pathological examination. Of three such patients identified, each patient had different presenting behavioral and/or aphasic characteristics. MRI, including DTI sequence in one patient, and FDG PET scan, revealed striking and dominant right temporal lobe atrophy, right corticospinal tract degeneration, and right temporal hypometabolism. Archived brain tissue was available in 2 patients; both demonstrating TDP-43 type 3 pathology (Mackenzie scheme) with predominant neuronal cytoplasmic inclusions. In one case, neurofibrillary tangles (Braak V) and neuritic plaques were also present in keeping with a diagnosis of Alzheimer's disease. There appears to be an association between FTD-MND and severe right temporal lobe atrophy. Until further characterization of such cases are determined, they may be best classified as right temporal variant FTD-MND.
Transcranial Magnetic Stimulation is non-invasive neuromodulation therapy which uses time-varying... more Transcranial Magnetic Stimulation is non-invasive neuromodulation therapy which uses time-varying magnetic fields to induce electric fields within the patient's brain, thus allowing for neural stimulation of the targeted region. While past studies have used Finite Element Analysis to model the effects of stimulation in brain tissue, there have been limited studies which analyze the effects of the same stimulation on the neuron responses. We use a python package called NEST to model populations of neurons which are healthy as well as those that have diminished or absent myelin sheath. We model diminished myelin sheath by increasing the capacitance of the neuron. We study the effects of Transcranial Magnetic Stimulation on the synaptic activity of these populations by utilizing clinical parameters specific to Transcranial Magnetic Stimulation. Furthermore, we compare our results to models of brain tissue stimulation using the Finite Element Analysis software Sim4Life. Our results indicate that all neuron populations, regardless of their myelination state, retain some stimulation threshold which increases discretely as the myelin sheath diminishes. Using tissue analysis, we also computed the range of TMS current necessary to reach these stimulation thresholds for demyelinated populations. Furthermore, we find that the maximum induced E-field on the cortical surface does not exceed 220 V/m for stimulation of highly demyelinated neuron populations. Therefore our study finds that although demyelinated neurons exhibit much lower nominal synaptic activity than healthy neurons, they are nevertheless responsive to Transcranial Magnetic Stimulation, and these stimulation thresholds can be reached without inducing an unsafe maximum E-field on the cortex.
Impaired insight into illness is commonly observed across various psychiatric illnesses, but is m... more Impaired insight into illness is commonly observed across various psychiatric illnesses, but is most frequent in patients with schizophrenia. The clinical relevance and public health impact of poor insight is reflected by its close association with important clinical outcome measures, such as treatment non-adherence, lower psychosocial functioning, poor prognosis, involuntary hospitalization, and higher utilization of emergency services. Although the neurobiology of insight has not been determined, data from neurocognitive and a few structural imaging studies provide some understanding of the neurobiological underpinnings of insight function in schizophrenia. Using published and preliminary data, we propose a hypothetical model of insight that may help initiate neurobiological investigations in this complex area.
Human Psychopharmacology-clinical and Experimental, May 15, 2023
IntroductionDespite frequent recognition of emotional blunting in the published literature, eithe... more IntroductionDespite frequent recognition of emotional blunting in the published literature, either as a primary symptom of depression or as an adverse effect of antidepressants, there is no systematic synthesis on this topic to our knowledge. We undertook this scoping review to assess the prevalence, clinical features, implicated causes and management of emotional blunting, outlining the phenomenological and clinical gaps in research.MethodA systematic search was done until March 15, 2022, to include all original studies (i.e., interventional trials, cohort & cross‐sectional studies, case reports, and case series). All reviewed data were delineated to answer pertinent clinical, phenomenological, and management questions related to the phenomenon of emotional blunting.ResultsA total of 25 original studies were included in our scoping review. Emotional blunting was described as a persistent diminution in both positive and negative feelings in depressed patients, who could subjectively differentiate it from their acute symptoms. However, the literature lacked the distinction between emotional blunting as a primary symptom of depression or an adverse effect of antidepressants. Common clinical strategies to manage antidepressant‐induced emotional blunting included dose reduction or switching to a different antidepressant.ConclusionEmotional blunting was a significant patient‐reported concern with antidepressants. Future research should clarify phenomenological and neurobiological constructs underlying emotional blunting to improve diagnostic and management skills.
Aim: To review genetic biomarkers of agranulocytosis and efficacy with clozapine as a screening t... more Aim: To review genetic biomarkers of agranulocytosis and efficacy with clozapine as a screening tool for the safe and effective use of clozapine. Methods: A PubMed search was performed using PRISMA guidelines for English articles. Separate searches were conducted using “clozapine” AND “agranulocytosis,” and “clozapine” AND (“response” OR efficacy “outcome”) AND “schizophrenia”. Eligible studies reported positive findings with genetic polymorphism(s) associated with clozapine-induced agranulocytosis (CIA) and clozapine’s efficacy. Case reports/series, abstracts, systematic reviews, and meta-analyses were excluded. Negative and genome-wide studies were not formally reviewed but included in the discussion. Results: Twelve out of 572 CIA studies and 32 out of 126 efficacy studies met the eligibility criteria for this review. Most reviewed studies were conducted in small samples of Jewish, Caucasian, and Asian populations using a candidate gene approach. Conclusion: Future research needs to address the limitations of the findings from the reviewed studies to enable a combined genetic screening for CIA and clozapine response to optimize the safe and effective use of clozapine without unnecessarily exposing potential clozapine nonresponders to CIA or neutropenia.
Hyperprolactinemia with low dose of risperidone in a young female To the Editor, Hyperprolactinem... more Hyperprolactinemia with low dose of risperidone in a young female To the Editor, Hyperprolactinemia is a widely recognized adverse effect of antipsychotic medications (APMs). However, most clinicians only monitor extrapyramidal symptoms (EPS) and not prolactin levels, unless adverse effects (AEs), such as sexual dysfunction, are reported. Although most patients treated with average doses of APMs do not develop significant EPS and/or hyperprolactinemia, few patients, especially those with secondary psychosis, can develop these AEs on low doses of APMs. This case discusses how a young Caucasian female with a previous diagnosis of schizophrenia developed significant AEs at a relatively low dose of an APM. History 21 year-old Caucasian female with history of schizophrenia, methamphetamine use, and fetal alcohol syndrome (FAS) was admitted to a state hospital due to worsening psychosis and agitation and continued methamphetamine use. She was being treated with 700 mg a day of quetiapine, which she refused to take due to dizziness and sedation. Patient was willing to be switched to risperidone but despite prolonged cross titration, patient still developed significant akathisia, which resulted in walking for hours and developing blisters on her feet. Patient also reported missing her menstrual periods and her prolactin level was significantly elevated at 135 ng/mL. After ruling out a prolactinoma, risperidone was gradually reduced from 2 mg to 1.5 mg/day and then to 1 mg/day but the level remained elevated at 127 ng/mL and 120 ng/mL, respectively (Table 1) with ongoing akathisia. We decided to gradually discontinue risperidone, within a few days of which, prolactin level normalized with complete resolution of akathisia without any rebound or relapse in psychosis. Discussion Unusual response to a relatively low dose of risperidone with significant EPS, hyperprolactinemia and amenorrhea, led us to
Efforts to improve insight have been ineffective or at best partially effective, which has arouse... more Efforts to improve insight have been ineffective or at best partially effective, which has aroused significant interest to investigate neural substrates for impaired insight in schizophrenia in an effort to develop better treatment strategies. In this context, several studies have revealed an association between impaired insight and deficits in midline and lateral cortical structures (
Patterns of atrophy in frontotemporal dementia (FTD) correlate with the clinical subtypes of beha... more Patterns of atrophy in frontotemporal dementia (FTD) correlate with the clinical subtypes of behavioral variant FTD (bvFTD), semantic dementia, progressive non-fluent aphasia (PNFA) and FTD with motor neuron disease (FTD-MND). Right temporal variant FTD is associated with behavioral dyscontrol and semantic impairment, with tau abnormalities more common in right temporal bvFTD and TDP-43 accumulation in right temporal semantic dementia. However, no clinical and anatomical correlation has been described for patients with predominant right temporal atrophy and FTD-MND. Therefore, we performed a database screen for all patients diagnosed with FTD-MND at Mayo Clinic and reviewed their MRI scans to identify those with striking, dominant, right temporal lobe atrophy. For cases with volumetric MRI we performed voxel based morphometry and for those with brain tissue we performed pathological examination. Of three such patients identified, each patient had different presenting behavioral and/or aphasic characteristics. MRI, including DTI sequence in one patient, and FDG PET scan, revealed striking and dominant right temporal lobe atrophy, right corticospinal tract degeneration, and right temporal hypometabolism. Archived brain tissue was available in 2 patients; both demonstrating TDP-43 type 3 pathology (Mackenzie scheme) with predominant neuronal cytoplasmic inclusions. In one case, neurofibrillary tangles (Braak V) and neuritic plaques were also present in keeping with a diagnosis of Alzheimer's disease. There appears to be an association between FTD-MND and severe right temporal lobe atrophy. Until further characterization of such cases are determined, they may be best classified as right temporal variant FTD-MND.
Transcranial Magnetic Stimulation is non-invasive neuromodulation therapy which uses time-varying... more Transcranial Magnetic Stimulation is non-invasive neuromodulation therapy which uses time-varying magnetic fields to induce electric fields within the patient's brain, thus allowing for neural stimulation of the targeted region. While past studies have used Finite Element Analysis to model the effects of stimulation in brain tissue, there have been limited studies which analyze the effects of the same stimulation on the neuron responses. We use a python package called NEST to model populations of neurons which are healthy as well as those that have diminished or absent myelin sheath. We model diminished myelin sheath by increasing the capacitance of the neuron. We study the effects of Transcranial Magnetic Stimulation on the synaptic activity of these populations by utilizing clinical parameters specific to Transcranial Magnetic Stimulation. Furthermore, we compare our results to models of brain tissue stimulation using the Finite Element Analysis software Sim4Life. Our results indicate that all neuron populations, regardless of their myelination state, retain some stimulation threshold which increases discretely as the myelin sheath diminishes. Using tissue analysis, we also computed the range of TMS current necessary to reach these stimulation thresholds for demyelinated populations. Furthermore, we find that the maximum induced E-field on the cortical surface does not exceed 220 V/m for stimulation of highly demyelinated neuron populations. Therefore our study finds that although demyelinated neurons exhibit much lower nominal synaptic activity than healthy neurons, they are nevertheless responsive to Transcranial Magnetic Stimulation, and these stimulation thresholds can be reached without inducing an unsafe maximum E-field on the cortex.
Impaired insight into illness is commonly observed across various psychiatric illnesses, but is m... more Impaired insight into illness is commonly observed across various psychiatric illnesses, but is most frequent in patients with schizophrenia. The clinical relevance and public health impact of poor insight is reflected by its close association with important clinical outcome measures, such as treatment non-adherence, lower psychosocial functioning, poor prognosis, involuntary hospitalization, and higher utilization of emergency services. Although the neurobiology of insight has not been determined, data from neurocognitive and a few structural imaging studies provide some understanding of the neurobiological underpinnings of insight function in schizophrenia. Using published and preliminary data, we propose a hypothetical model of insight that may help initiate neurobiological investigations in this complex area.
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