Tryptophan hydroxylase 1 gene haplotypes modify the effect of a hostile childhood environment on adulthood harm avoidance

We conducted a series of tests to determine whether there is any association between tryptophan hydroxylase 1 (TPH1) and temperament in adulthood. In addition to testing for main effects, we investigated whether TPH1 gene variation modifies the influence of childhood environment on temperament in adulthood. The subjects were 341 healthy adults whose childhood environment was assessed by their mothers in 1980 and who self-rated their temperaments twice, in 1997 and 2001. We found no association between the TPH1 gene and temperament; however, among women, the TPH1 gene modified a relationship between adverse childhood environment and harm avoidance in adulthood. This finding was confirmed in the same sample in another test setting 4 years later. The presence of the A/A haplotype of the TPH1 intron 7 A218A and A779C polymorphism predicted a high level of adulthood harm avoidance in the presence of a hostile childhood environment as defined in terms of emotional rejection, maternal neglect and harsh and inconsistent discipline. In addition, the findings suggest a gene-environment correlation for novelty seeking in men.     

Cloninger's temperament dimensions and epidermal growth factor A61G polymorphism in Finnish adults

This study examines a link between human temperament and epidermal growth factor (EGF). There is evidence that dopaminergic neurotransmission in the central nervous system has a role in temperament, especially in novelty seeking. Functional polymorphism in EGF gene has an impact on EGF production, and EGF, in turn, appears to affect the development of midbrain dopaminergic neurons. Epidermal growth factor gene A61G polymorphisms were studied in a randomly selected sample of 292 Finnish adults. Their temperaments were assessed twice (with a 4-year test-retest interval) with Cloninger's Temperament and Character Inventory consisting of four dimensions, i.e. novelty seeking (NS), harm avoidance (HA), reward dependence (RD) and persistence (P). The findings on men showed a significant association between a presence of the G/G polymorphism and scoring in the highest tertile on NS in both test and retest. The same was true with men who scored high on RD, especially on sensitivity, in both tests. Among women, G/G polymorphism was associated with a stable high level of P. Importantly, temperament dimensions, as assessed with one test only, did not provide replicable associations with EGF polymorphism across the two measurements. Our results demonstrate the importance of reliable phenotype assessment and lend support to the hypothesis that dopaminergic activity is one factor underlying stable temperament.     

The brain-derived neurotrophic factor Val66Met polymorphism modulates the effects of parental rearing on personality traits in healthy subjects

There is a growing body of data suggesting that gene-environment interaction is critical in the characterization of personality traits; however, previous studies have not taken into consideration variability in parental rearing as an environmental factor. In this study, we examined the effects of the interaction between the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and parental rearing on personality traits in 710 healthy Japanese subjects. Perceived parental rearing was assessed by the Parental Bonding Instrument (PBI), which consists of the care and protection factors. Assessment of personality traits was performed by the temperament and character inventory (TCI), which has seven dimensions, i.e. novelty seeking, harm avoidance, reward dependence, persistence, self-directedness, cooperativeness and self-transcendence. Parental rearing has significant main effects on some TCI dimensions, but no significant main effects of the BDNF genotype on the TCI scores were found. The interaction between the BDNF genotype and maternal care of the PBI had significant effects on harm avoidance and self-directedness of the TCI. Post hoc analyses showed that decreased maternal care was correlated with increased harm avoidance and decreased self-directedness, and for both personality traits the partial correlation coefficient was highest in the Met/Met genotype group and lowest in the Val/Val genotype group and the value of the Val/Met genotype group was in the middle. Data from this study suggest that the BDNF Val66Met polymorphism modulates the effects of parental rearing, especially maternal care, on harm avoidance and self-directedness in healthy subjects.     

Memories and traces. From Jewish exilists' authoritarian personality research via Cloninger's psychobiology of personality traits to a neurobiological approach to conflict management

Research on personality as a useful construct to understand people's behavior in conflict situations was traced over more than fifty years, and an attempt was made to add neurobiological parameters to psycho-socio-cultural approaches. As a starting point, scientists in exile have been called to mind who had been expelled from Nazi Germany for their Jewish origins. Among them were Adorno and Frenkel-Brunswik whose extensive studies on the authoritarian personality structure were quoted. In their work, personality was defined as a more or less enduring organisation of forces within the individual helping to determine responses in various situations, which is responsible for consistency in behavior. As a next step, Cloninger's psychobiology of personality traits was presented. In his personality concept, four temperamental traits (novelty seeking, harm avoidance, reward dependency and persistence) and three character dimensions are included. Temperamental traits are heritable, developmentally stable, emotionally based, uninfluenced by social learning, and linked to specific brain biological features. The temperaments have a certain neuroendocrinological feature which can be determined. Character dimensions develop in a stagelike process from infancy to adulthood and are influenced by temperament, social learning, genetic factors, and random life events. Personality is still considered a useful theoretical approach to conflict management research and practice. A neurobiological point of view seems to be a useful supplementation in addition to traditional psycho-socio-cultural approaches. Measuring biological compounds can supply the conflict manager with an additional tool of knowledge enhancing the ability to understand and anticipate conflict behavior.     

Polymorphism of the serotonin 2A receptor gene (5HTR2A) and personality traits

The interindividual variation of temperament features (such as anxiety, neuroticism, harm avoidance) is determined, in particular, by allele polymorphism of genes involved in serotonin metabolism and has earlier been associated with the insertion/deletion polymorphism of the serotonin transporter gene. Polymorphic alleles of the serotonin 2A receptor gene (5HTR2A) were tested for association with personality traits assessed with several tests. The T102C and A1438G polymorphisms were associated with a variation in emotionality, activity, and sociability, which are integral characteristics of temperament. With each polymorphism, differences were significant only between heterozygotes and homozygotes. Carriers of T102C genotype A1/A2 displayed a lower level of anxiety-related traits, a higher score on scale Hypomania, and a lower score on scale Social Introversion and were assumed to have higher activity and sociability. Carriers of A1428G genotype A/G differed from homozygotes G/G in having a lower level of social introversion and a lower score on scale No close friends, which testified to higher sociability of heterozygotes. Thus, the polymorphic alleles of SHTR2A proved to be associated with personality traits in mentally healthy people.     

Altered response to neuroendocrine challenge linked to indices of the metabolic syndrome in healthy adults

Metabolic syndrome (MetS) is characterized by central obesity, hypertension, insulin resistance, and hypercholesterolemia. Hypothalamic-pituitary-adrenal (HPA) axis activity is frequently abnormal in MetS, and excessive cortisol exposure may be implicated in metabolic derangements. We investigated the hypothesis that cortisol and adrenocorticotropic hormone (ACTH) responses to a standardized neuroendocrine challenge test would be associated with indices of MetS in a community sample of healthy adults. Healthy adults, 125 men and 170 women, without significant medical problems or chronic medications were recruited from the community. Participants completed the dexamethasone/corticotropin-releasing hormone (Dex/CRH) test, and anthropometric measurements, blood pressure, glycosylated hemoglobin (HbA1c), and cholesterol were measured. Participants reported on their history of early life stress and recent stress, as well as mood and anxiety symptoms. Cortisol and ACTH responses to the Dex/CRH test were negatively associated with measures of central adiposity (p<0.001) and blood pressure (p<0.01), and positively associated with HDL cholesterol (p<0.01). These findings remained significant after controlling for body mass index (BMI). Measures of stress and anxiety and depressive symptoms were negatively correlated with cortisol and ACTH responses in the Dex/CRH test but were not related to MetS indices. That altered HPA axis function is linked to MetS components even in a healthy community sample suggests that these processes may be involved in the pathogenesis of MetS. Identification of premorbid risk processes might allow for detection and intervention prior to the development of disease.     

Genetics of early cancer detection behaviours in Australian female twins.

Early detection of cervical and breast cancers is an important component of women's health strategy. Screening programmes, health professional interventions and preventive behaviours such as breast self-examination provide the means to this end. Our twin study sought to identify the relative influence of environmental and genetic factors on liability to early cancer detection behaviours, including use of cervical smear tests, mammograms, and breast examination. Additive genetic and random environmental effects models gave the best, most parsimonious fit to the data for each early cancer detection behaviour. The heritability of liability to Pap smear use was 66%, mammogram use 50%, breast examination by a doctor or nurse 38% and breast self-examination 37%. Genetic influences were behaviour-specific; there was no evidence for a common genetic influence on the four behaviours. Potential covariates investigated included age, amount of contact between co-twins, educational level and personality traits such as harm avoidance, novelty seeking, reward dependence, neuroticism, anxiety, depression, self-esteem, perceived control, interpersonal dependency and ways of coping. None were significant. The study was carried out before the implementation of national screening programmes with media campaigns to increase participation rates. Hence follow-up investigation, including data on regularity of behaviours, would be informative.     

Polymorphism of the Serotonin 2A Receptor Gene (5HTR2A) and Personality Traits

The individual variation of temperament features (such as anxiety, neuroticism, harm avoidance) is determined, among other things, by allele polymorphism of genes involved in serotonin metabolism and has earlier been associated with the insertion/deletion polymorphism of the serotonin transporter gene. Polymorphic alleles of the serotonin 2A receptor gene (5HTR2A) were tested for association with personality traits assessed in several tests. The T102C and A1438G polymorphisms were associated with variation in emotionality, activity, and sociability, which are integral characteristics of temperament. With each polymorphism, differences were significant only between heterozygotes and homozygotes. Carriers of T102C genotype A1/A2 displayed a lower level of anxiety-related traits, a higher score on the Hypomania scale, and a lower score on the Social Introversion scale and were assumed to have higher activity and sociability. Carriers of A1438G genotype A/G differed from homozygotes G/G in having a lower level of social introversion and a lower score on the No Close Friends scale, which testified to higher sociability of heterozygotes. Thus, the polymorphic alleles of 5HTR2A proved to be associated with personality traits in mentally healthy people.     

Functional characteristics of the bovine hypothalamic-pituitary-adrenal axis vary with temperament

Hypothalamic-pituitary-adrenal (HPA) axis function, in Brahman heifers of differing temperament, was evaluated using separate challenges with CRH and ACTH. Exit velocity (EV) measurement was used to classify heifer temperament as calm [C; consisted of 6 slowest heifers (EV=1.05+/-0.05 m/s)] or temperamental [T; 6 fastest heifers (EV=3.14+/-0.22 m/s)]. During the 6 h prior to CRH challenge, areas under the ACTH (P=0.025) and cortisol (P<0.001) curves were greater in the temperamental heifers. Baseline cortisol (P<0.001) but not ACTH (P=0.10) differed between temperament groups. Following CRH challenge, areas under the ACTH (P=0.057) and cortisol (P<0.01) response curves were greater in the calm animals. The same animals were subjected to an ACTH challenge 14 d following their utilization in the CRH stimulation experiment. Prior to ACTH challenge, baseline cortisol concentrations were higher (P<0.001) in the temperamental heifers (T=18+/-2.6, C=4.3+/-0.6 ng/mL). Following ACTH administration, area under the cortisol response curve was greater (P=0.07) in the calm heifers. After declining below baseline concentrations during the post-challenge recovery period, cortisol in temperamental animals was again greater (P=0.02) than in the calm heifers. These data demonstrate that cattle with an excitable temperament exhibit increased stress responsiveness to handling, increased baseline adrenal function but not increased basal pituitary function, and a muted responsiveness to pharmacological stimulus. Thus, functional characteristics of the HPA axis vary with animal temperament.     

The role of anxious and hyperthymic temperaments in mental disorders: a national epidemiologic study

Temperament has been demonstrated clinically to be linked to mental disorders. We aimed to determine the possible role of temperament in mental disorders in a national epidemiologic study. A nationally representative sample of adults (n=1320) was administered the Lebanese-Arabic version of the Temperament Evaluation of the Memphis, Pisa, Paris and San Diego Autoquestionnaire (TEMPS-A), and the Arabic CIDI 3.0, as part of the LEBANON study. The association among temperaments and DSM-IV mood, anxiety, and impulse control disorders was assessed. The anxious temperament was shown to be a robust predictor of most disorders, especially within the anxiety and depressive clusters. The hyperthymic temperament had a uniquely protective effect on most mental disorders, with the exception of separation anxiety, bipolar, substance abuse and impulse control disorders. These effects were moderated by age and education. Temperaments, previously largely neglected in epidemiologic studies, could play a major role in the origin of mental disorders.     

Associations between Neuroticism and Depression in Relation to Catastrophizing and Pain-Related Anxiety in Chronic Pain Patients

Several cognitive-affective constructs, including pain catastrophizing and pain-related anxiety, have been implicated in the onset and progression of chronic pain, and both constructs have been identified as key targets for multidisciplinary pain treatment. Both neuroticism and depression have been linked to these constructs (and to each other), but how each may contribute to the pain experience is unknown. This study tested associations between neuroticism, depression, and indices of catastrophizing and pain-related anxiety among persons seeking treatment for chronic non-malignant pain. We hypothesized, as a higher-order personality trait, neuroticism would remain uniquely associated with both pain catastrophizing and pain-related anxiety, even after accounting for current symptoms of depression. A retrospective study design assessed depression (as measured by the Centers for Epidemiologic Studies-Depression scale), neuroticism (measured with the Neuroticism-Extraversion-Openness Personality Inventory), the Pain Catastrophizing Scale, and the Pain Anxiety Symptom Score in a consecutive series of patients (n=595) admitted to a 3-week outpatient pain treatment program from March 2009 through January 2011. Hierarchical regression indicated that neuroticism was independently associated with greater pain catastrophizing and pain-related anxiety, above-and-beyond the contributions of sociodemographic characteristics, pain severity, and depression. A depression by neuroticism interaction was not observed, suggesting that associations between neuroticism and cognitive-affective pain constructs remained stable across varying levels of current depression. These findings represent an early but important step towards the clarification of complex associations between trait neuroticism, current depression, and tendencies toward catastrophic and anxiety-provoking appraisals of pain among persons seeking treatment for chronic pain.     

Mouse model of the human serotonin transporter-linked polymorphic region

Genetic factors play a significant role in risk for mood and anxiety disorders. Polymorphisms in genes that regulate the brain monoamine systems, such as catabolic enzymes and transporters, are attractive candidates for being risk factors for emotional disorders given the weight of evidence implicating monoamines involvement in these conditions. Several common genetic variants have been identified in the human serotonin transporter (5-HTT) gene, including a repetitive sequence located in the promoter region of the locus called the serotonin transporter-linked polymorphic region (5-HTT-LPR). This polymorphism has been associated with a number of mental traits in both humans and primates, including depression, neuroticism, and harm avoidance. Some, but not all, studies found a link between the polymorphism and 5-HTT levels, leaving open the question of whether the polymorphism affects risk for mental traits via changes in 5-HTT expression. To investigate the impact of the polymorphism on gene expression, serotonin homeostasis, and behavioral traits, we set out to develop a mouse model of the human 5-HTT-LPR. Here we describe the creation and characterization of a set of mouse lines with single-copy human transgenes carrying the short and long 5-HTT-LPR variants. Although we were not able to detect differences in expression between the short and long variants, we encountered several technical issues concerning the design of our humanized mice that are likely to have influenced our findings. Our study serves as a cautionary note for future studies aimed at studying human transgene regulation in the context of the living mouse.

     

Netherlands twin family study of anxious depression (NETSAD).

In a longitudinal study of Dutch adolescent and young adult twins, their parents and their siblings, questionnaire data were collected on depression, anxiety and correlated personality traits, such as neuroticism. Data were collected by mailed surveys in 1991, 1993, 1995 and 1997. A total of 13,717 individuals from 3344 families were included in the study. To localise quantitative trait loci (QTLs) involved in anxiety and depression, the survey data were used to select the most informative families for a genome-wide search. For each individual a genetic factor score was computed, based on a genetic multivariate analysis of anxiety, depression, neuroticism and somatic anxiety. A family was selected if at least two siblings (or DZ twins) had extreme factor scores. Both discordant (high-low) and concordant (high-high and low-low) pairs were included in the selected sample. Once an extreme sibling pair was selected, all family members (parents and additional siblings of the selected pair) who had at least once returned a questionnaire booklet were asked to provide a DNA sample. In total, 2724 individuals from 563 families (1007 parents and 1717 offspring) were approached and 1975 individuals from 479 families (643 patients and 1332 offspring) complied by returning a buccal swab for DNA isolation. All offspring from selected families were asked to participate in a psychiatric interview and in a 24-hour ambulatory assessment of cardiovascular parameters and cortisol. The interview consisted of the WHO-Composite International Diagnostic Interview and was administered to 1253 offspring. In this paper we describe the genetic-epidemiological analyses of the survey data on anxiety, somatic anxiety, neuroticism and depression. We detail how these data were used to select families for the QTL study and discuss strategies that may help elucidate the molecular pathways leading from genes to anxious depression.     

Childhood adversity and epigenetic modulation of the leukocyte glucocorticoid receptor: preliminary findings in healthy adults

Background

A history of early adverse experiences is an important risk factor for adult psychopathology. Changes in stress sensitivity and functioning of the hypothalamic-pituitary-adrenal (HPA) axis may underlie the association between stress and risk for psychiatric disorders. Preclinical work in rodents has linked low levels of maternal care to increased methylation of the promoter region of the glucocorticoid receptor (GR) gene, as well as to exaggerated hormonal and behavioral responses to stress. Recent studies have begun to examine whether early-life stress leads to epigenetic modifications of the GR gene in humans.

Methods

We examined the degree of methylation of a region of the promoter of the human GR gene (NR3C1) in leukocyte DNA from 99 healthy adults. Participants reported on their childhood experiences of parental behavior, parental death or desertion, and childhood maltreatment. On a separate day, participants completed the dexamethasone/corticotropin-releasing hormone (Dex/CRH) test, a standardized neuroendocrine challenge test.

Results

Disruption or lack of adequate nurturing, as measured by parental loss, childhood maltreatment, and parental care, was associated with increased NR3C1 promoter methylation (p<.05). In addition, NR3C1 promoter methylation was linked to attenuated cortisol responses to the Dex/CRH test (p<.05).

Conclusions

These findings suggest that childhood maltreatment or adversity may lead to epigenetic modifications of the human GR gene. Alterations in methylation of this gene could underlie the associations between childhood adversity, alterations in stress reactivity, and risk for psychopathology.     

Temperament clusters in a normal population: implications for health and disease

Background

The object of this study was to identify temperament patterns in the Finnish population, and to determine the relationship between these profiles and life habits, socioeconomic status, and health.

Methods/Principal Findings

A cluster analysis of the Temperament and Character Inventory subscales was performed on 3,761 individuals from the Northern Finland Birth Cohort 1966 and replicated on 2,097 individuals from the Cardiovascular Risk in Young Finns study. Clusters were formed using the k-means method and their relationship with 115 variables from the areas of life habits, socioeconomic status and health was examined.

Results

Four clusters were identified for both genders. Individuals from Cluster I are characterized by high persistence, low extravagance and disorderliness. They have healthy life habits, and lowest scores in most of the measures for psychiatric disorders. Cluster II individuals are characterized by low harm avoidance and high novelty seeking. They report the best physical capacity and highest level of income, but also high rate of divorce, smoking, and alcohol consumption. Individuals from Cluster III are not characterized by any extreme characteristic. Individuals from Cluster IV are characterized by high levels of harm avoidance, low levels of exploratory excitability and attachment, and score the lowest in most measures of health and well-being.

Conclusions

This study shows that the temperament subscales do not distribute randomly but have an endogenous structure, and that these patterns have strong associations to health, life events, and well-being.     

Corticotropin-releasing hormone in depression and post-traumatic stress disorder

Corticotropin-releasing hormone (CRH) has been implicated in the regulation of a wide range of behaviors including arousal, motor function, feeding, and reproduction. Because depressed patients are often hypercortisolemic and intracerebroventricular administration of CRH to experimental animals produces a syndrome reminiscent of depression, dysregulation of this compound has been suggested to be involved in the pathogenesis of depressive and anxiety disorders. Studies of cerebrospinal fluid CRH levels and clinical neuroendocrine tests in patients with anxiety and affective disorders have supported this hypothesis. This review discusses these neuroendocrine findings in melancholic and atypical depression as well as post-traumatic stress disorder (PTSD). Overall, the data suggest that melancholic depression is characterized by hyperactive central CRH systems with overactivity of the pituitary-adrenal (HPA) axis. On the other hand, atypical depression is characterized by hypoactive central CRH systems and accompanying underactivity of the hypothalamic-pituitary-adrenal axis. Furthermore, the neuroendocrinology of PTSD appears to be unique, in that patients have hyperactive central CRH systems with underactivity of the pituitary-adrenal axis.     

The Influence of the Val158Met Catechol-O-Methyltransferase Polymorphism on the Personality Traits of Bipolar Patients

Introduction

Certain personality traits and genetic polymorphisms are contributing factors to bipolar disorder and its symptomatology, and in turn, this syndrome influences personality. The aim of the present study is to compare the personality traits of euthymic bipolar patients with healthy controls and to investigate the effect of the catechol-O-methyltransferase (COMT) Val158Met genotype on those traits. We recruited thirty seven bipolar I patients in euthymic state following a manic episode and thirty healthy controls and evaluated their personality by means of the Cloninger’s Temperament and Character Inventory (version TCI-R-140). We assessed the influence of the polymorphism Val158Met in the COMT gene on the personality of these patients. The patients scored higher than controls in harm avoidance (61.3±12.5 vs. 55.3±8.1) and self-transcendence (45.3±12.8 vs. 32.7±8.2) and scored lower than controls in self-directedness (68.8±13.3 vs. 79.3±8.1), cooperativeness (77.1±9.1 vs. 83.9±6.5) and persistence (60.4±15.1 vs. 67.1±8.9). The novelty seeking dimension associates with the Val158Met COMT genotype; patients with the low catabolic activity genotype, Met/Met, show a higher score than those with the high catabolic activity genotype, Val/Val.

Conclusions

Suffering from bipolar disorder could have an impact on personality. A greater value in harm avoidance may be a genetic marker for a vulnerability to the development of a psychiatric disorder, but not bipolar disorder particularly, while a low value in persistence may characterize affective disorders or a subgroup of bipolar patients. The association between novelty seeking scores and COMT genotype may be linked with the role dopamine plays in the brain’s reward circuits.     

Association of Mood Disorders with Serum Zinc Concentrations in Adolescent Female Students

Among various factors influencing mood disorders, the impact of micronutrient deficiencies has attracted a great attention. Zinc deficiency is considered to play a crucial role in the onset and progression of mood disorders in different stages of life. The main objective of this study was to assess the correlation between serum zinc levels and mood disorders in high school female students. This cross-sectional study was conducted on a random sample of 100 representative high school female students. The participants completed 24-h food recall questionnaires to assess the daily zinc intakes. Serum zinc status was assessed using flame atomic absorption spectrometry, and zinc deficiency was defined accordingly. Mood disorders were estimated by calculating the sum of two test scores including Beck’s depression inventory (BDI) and hospital anxiety depression scale (HADS) tests. General linear model (GLM) and Pearson’s regression test were applied to show the correlation of serum zinc levels and mood disorder scores and the correlation between zinc serum levels and BDI scores, respectively. Dietary zinc intake was higher in subjects with normal zinc concentrations than that of zinc-deficient group (p = 0.001). Serum zinc levels were inversely correlated with BDI and HADS scores (p < 0.05). Each 10 μg/dL increment in serum zinc levels led to 0.3 and 0.01 decrease in depression and anxiety scores, respectively (p < 0.05). Serum zinc levels were inversely correlated with mood disorders including depression and anxiety in adolescent female students. Increasing serum levels of zinc in female students could improve their mood disorders.     

An update on molecular genetic studies of human personality traits

Personality is a complex phenotype and people differ considerably when they are evaluated by self-report questionnaires. There is convincing evidence from twin studies that basic personality dimensions in men and women have a considerable genetic component. However, only recently have common genetic polymorphisms been associated with particular personality traits, especially the dopamine D4 receptor with novelty seeking and the serotonin transporter with anxiety-related traits or neuroticism. The current review examines progress in the past few years in molecular personality genetics and focuses on the reasons for difficulties in replicating first findings as well as the prospects for future studies in this area. The molecular genetic structure of human personality is worth studying both for its intrinsic interest in helping us to understand individual differences in human behaviour and the light it will shed on more complex behavioural disorders that are likely to partially share some common genetic variants.     

Ten ways to improve the treatment of depression and anxiety in adults

Complaints of depression and anxiety are very common among adult patients seeking treatment in primary care settings, and primary care providers prescribe the majority of medications for these conditions. Psychiatrists are often asked to evaluate and manage patients with major depression or anxiety disorders who have not improved after treatment in primary care.We highlight ten frequently overlooked aspects of the care of patients who present with depression and anxiety in primary care. Chief among these aspects is the consideration of a thorough differential diagnosis, particularly bipolar disorder, psychotic disorders, dementia and substance abuse, each of which requires specific treatment approaches. Additional considerations include avoidance of medications or doses that may aggravate anxiety symptoms and regular follow-ups to assess symptomatic and functional improvement. Finally, it is important to actively manage the treatment through dose escalation, switching medications or employing additional treatment components until remission is achieved.Judicious use of benzodiazepine clonazepam and appropriate referrals to psychotherapy can contribute to optimal treatment outcomes.