Apathy associated with antidepressant drugs: a systematic review.

OBJECTIVES: Administration of antidepressant drugs - principally selective serotonin reuptake inhibitors (SSRIs) - may induce clinically significant 'apathy' which can affect treatment outcomes adversely. We aimed to review all relevant previous reports. METHODS: We performed a PUBMED search of English-language studies, combining terms concerning psychopathology (e.g. apathy) and classes of antidepressants (e.g. SSRI). RESULTS: According to certain inclusion (e.g. use of DSM/ICD diagnostic criteria) and exclusion (e.g. presence of a clinical condition that may induce apathy) criteria, 50 articles were eligible for review. Together, they suggest that administration of antidepressants - usually SSRIs - can induce an apathy syndrome or emotional blunting, i.e. a decrease in emotional responsiveness, to circumstances which would have triggered intense mood reactions prior to pharmacotherapy. The reported prevalence of antidepressant-induced apathy ranges between 5.8 and 50%, and for SSRIs ranges between 20 and 92%. Antidepressant-induced apathy emerges independently of diagnosis, age, and treatment outcome and appears dose-dependent and reversible. The main treatment strategy is dose reduction, though some data suggest the usefulness of treatment with olanzapine, bupropion, agomelatine or amisulpride, or the methylphenidate-modafinil-olanzapine combination. CONCLUSION: Antidepressant-induced apathy needs careful clinical attention. Further systematic research is needed to investigate the prevalence, course, aetiology, and treatment of this important clinical condition.

Correlations of plasma oxytocin with clinical and hormonal parameters in panic disorder.

AIMS: The potential association between oxytocin (OXT) plasma levels and clinical and hormonal parameters in panic disorder (PD) especially in its acute phase - has not been investigated as yet. This was the aim of this article. METHOD: Twenty-four consecutively-referred, acutely-ill, medication-free PD patients with (PDA, N = 21) or without agoraphobia, moreover without comorbidities, completed the following clinical measures: Hamilton Anxiety Rating Scale (HARS); Agoraphobic Cognitions Questionnaire (ACQ); Mobility Inventory-Alone subscale (MI-alone); and number of panic attacks during last 21 d (PA21d). Plasma levels of OXT, adrenocorticotropic hormone (ACTH) and cortisol were evaluated. RESULTS: OXT levels were significantly, negatively associated with the HARS scores (r= -0.59 p=.002) and weakly, negatively correlated with the ACQ scores (r = -0.403 p=.051). No significant correlations were traced between OXT levels and PA21d, MI-alone, ACTH, and cortisol. CONCLUSION: In acutely-ill, medication-free PD patients, OXT plasma levels may be relevant to the severity of their 'general' anxiety symptoms, but not to the 'specific' panic psychopathology.

Cholesterol levels in plasma and cerebrospinal fluid in patients with clinically isolated syndrome and relapsing-remitting multiple sclerosis.

Cholesterol is essential for myelin formation, but may also modulate mechanisms involved in adaptive immune responses. It is unclear whether lack of remyelination in multiple sclerosis (MS) results from an insufficient capacity of oligodendrocyte precursor cells to differentiate or from cholesterol insufficiency. Several studies have assessed the potential association of lipid profile and its metabolism with demyelination, disability, and disease progression. The aim of the present study was to measure cholesterol levels in plasma and cerebrospinal fluid (CSF) of patients with relapsing remitting MS (RRMS) or with clinically isolated syndrome (CIS), and to investigate whether there is an association between cholesterol levels and disease characteristics. Sixty-two patients with CIS and 46 patients with RRMS were included in the study. All patients had low EDSS and were medication-free at assessment. Forty-eight subjects within the same age range served as controls. Cholesterol concentrations were measured in plasma and in CSF by the same enzymatic - colorimetric method, and were related to clinical status, disease activity in magnetic resonance imaging (MRI) and presence of oligoclonal bands in CSF (OBs). Significantly lower levels of plasma and CSF cholesterol were found in patients compared to controls. Patients with OBs showed significantly lower levels of CSF cholesterol but not plasma cholesterol compared to OBs-negative patients. A positive correlation of plasma cholesterol with age and of CSF cholesterol with EDSS was found. Our results suggest that low CSF cholesterol in MS patients with positive OBs might reflect extensive demyelination and a more aggressive disease course associated with an increased humoral immune response against membrane components.

Pituitary-adrenal axis hormones in early-onset versus late-onset panic disorder.

OBJECTIVE: It has been hypothesised that early-onset panic disorder (PD) may constitute a biologically distinct subtype of PD, but the few relevant data are inconclusive. We systematically explored for potential psychopathological and hormonal differences between early-onset (age at onset ≤ 27 years) versus late-onset PD, in consecutively-referred, medication-free, acutely-ill PD outpatients, moreover without comorbid mental disorders except agoraphobia (N = 54; age = 32.3 ± 7.5 years; early-onset = 27; females = 38). METHODS: Hormones assessed (plasma levels) included adrenocorticotropic hormone (ACTH), cortisol and dehydroepiandrosterone sulphate (DHEAS). Psychopathological measures included panic attacks' number during last three weeks, the Agoraphobic Cognitions and the Body Sensations Questionnaires and the Hamilton Anxiety Rating Scale. RESULTS: Early-onset PD patients - compared to their late-onset counterparts - had longer duration of the disease. The two onset-groups demonstrated similar panic and anxiety symptoms and similar ratios of smokers/never-smokers. However, early-onset patients demonstrated significantly greater ACTH and DHEAS levels and higher (marginally significant) cortisol levels than the late-onset patients. Moreover, in the early-onset patients only, significant positive correlations emerged between ACTH levels and the severity of both panic and anxiety symptomatology. CONCLUSIONS: These findings suggest that the two onset-groups demonstrate significant differences in the hypothalamic-pituitary-adrenal axis functioning, at least when acutely-ill.Key pointsEarly-onset panic disorder (EOPD) may differ biologically from late-onset PD (LOPD).EOPD was correlated with greater adrenocorticotropic hormone (ACTH) plasma levels.EOPD was correlated with greater dehydroepiandrosterone sulphate plasma levels.In EOPD only, ACTH levels were positively correlated with panic and anxiety symptoms.

Stress Hormones as Predictors of Response to Cognitive Behavior Therapy in Panic Disorder.

OBJECTIVE: Data regarding the potential association between the outcome of psychotherapy of panic disorder (PD) and biological parameters are few. In 21 (16 females) consecutively referred, medication-free, acutely ill PD outpatients, without comorbidities, except agoraphobia, we systematically explored for potential neuroendocrine and clinical correlates of response to a brief cognitive behavior therapy (CBT). METHODS: Cortisol and adrenocorticotropic hormone (ACTH) basal plasma levels were measured. Measures of psychopathology: (a) Symptom Checklist-90-Revised (SCL-90-R), (b) Clinical Global Impressions-Improvement (CGI-I) Scale, (c) Agoraphobic Cognitions Questionnaire (ACQ), and (d) Mobility Inventory (MI)-alone subscale. RESULTS: Nonresponders to CBT (CGI-I >2; N = 6) - as compared to the responders (CGI-I ≤2; N = 15) - demonstrated significantly higher cortisol and ACTH basal plasma concentrations. These differences were much stronger when only female patients (nonresponders = 4; responders = 12) were taken into consideration. Regarding psychopathology, nonresponders to CBT suffered from more severe agoraphobia (MI-alone) at baseline. On the contrary, more intense manifestations of anger (SCL-90-R) at baseline were associated with a better treatment outcome. Response to CBT was associated with significant reductions in all SCL-90-R subscales, more pronounced for "phobic anxiety" and "anxiety" subscales. CONCLUSIONS: This study suggests that in acutely ill, medication-free PD patients, response to CBT may be associated with certain hormonal and clinical parameters at baseline.

Psychiatric diagnosis, gender, aggression, and mode of attempt in patients with single versus repeated suicide attempts.

There is evidence that patients with multiple suicide attempts in their history are at greater risk to repeat attempt and eventually die by suicide compared to those with a single attempt. This cross-sectional study aimed to explore possible differences in clinical characteristics between patients with a single attempt and patients with repeated attempts. Two hundred thirty one patients hospitalised in psychiatric department after suicide attempt were studied. Comparisons were made in relation to age, gender, psychiatric diagnosis, aggression, depression severity, suicide intent and mode of attempt. Highest frequencies of patients with repeated attempts were found for bipolar disorder (69%) and lowest for adjustment/personality disorders (39%). In patients with repeated attempts, female gender was associated with non-violent attempt mode. Depressive symptomatology was higher in patients with repeated attempts among females. In patients with depression those with repeated attempts were younger than patients with single attempt. In patients with mood disorders, total aggression and hostility scores were higher in females with repeated attempts but not in males. Psychiatric diagnosis, gender and attempt mode are features that differentiate patients with single and repeated attempts and should be considered to identify patients at increased risk to repeat attempt and design effective prevention interventions.

Associations of plasma testosterone with clinical manifestations in acute panic disorder.

The probable implication of testosterone in the neurobiology of anxiety disorders, and particularly panic disorder (PD), is poorly studied. We explored for potential differences concerning testosterone (T) plasma levels and the ratio testosterone/cortisol (T/C) between medication-free, consecutively-referred patients with acute exacerbation of PD comorbid with agoraphobia (PDA) (N = 40; females = 24; age = 31.4 ± 7.1 years) and healthy controls (N = 80; females = 48; matched for age). Moreover, we investigated for potential associations of T levels and T/C ratio with the severity of acute PDA psychopathology in the patients of the sample. Psychometric measures included panic attacks' number during last three weeks (PA-21days), the Agoraphobic Cognitions Questionnaire (ACQ) and the Hamilton Anxiety Rating Scale (HARS). Male patients -but not female ones- demonstrated significantly lower T levels compared to controls. Moreover, in male patients, a significant inverse association emerged between T/C ratio and PA-21days, so that lower T/C ratio is associated with significantly more panic attacks. On the contrary, female patients demonstrated significant positive associations: (a) between T levels and PDA-related pathological cognitions (ACQ); (b) between the T/C ratio and both PA-21days and anxiety symptoms' severity (HARS). The results of the study suggest that testosterone is significantly associated to the severity of clinical manifestations of acute panic disorder, although in a different fashion concerning the two genders.

Clinical and psychometric features of psychiatric patients after a suicide attempt in relation with menstrual cycle phases.

There is evidence that frequency of suicide attempts of fertile women is related to the menstrual cycle phases, while the influence of hormonal and psychiatric features has been hypothesized. This study aims to explore the distribution and possible differences in clinical characteristics of women who attempted suicide in relation to menstrual cycle. Seventy fertile female psychiatric patients, hospitalized in psychiatric department after a suicide attempt, were studied. Depression was assessed using Beck Depression Inventory, suicide intent with the Suicide Intent Scale, and aggression using the Buss-Perry Aggression Questionnaire. A profile of psychopathology was obtained by using Symptom Check List SCL-90-R. Attempts were more frequent during the last 4 days of luteal phase and during the 4 days of menses, with 59% of attempts to occur during these 8 days. Patterns of number of attempts and cycle phase were similar for subgroups regarding diagnosis, violent/non-violent mode of suicide attempt, and one or repeated attempts. Although attempts were unequally distributed during the cycle, none of the psychiatric features assessed in the present study were related to the higher frequency of attempts during premenstrual/menstrual days, indicating the need to include additional aspects of suicidal behavior in future studies.

Body mass index and plasma leptin in psychiatric suicide attempters.

OBJECTIVES: To evaluate body mass index (BMI) and its correlate plasma leptin levels that have been associated with psychiatric morbidity and suicidal behaviour, in relation to clinical features in psychiatric patients after a suicide attempt. METHODS: BMI and plasma leptin were assessed in 198 patients (66 males, age range of 21 to 80 years) who were admitted to the hospital after a suicide attempt, 98 with major depressive disorder, 28 with bipolar disorder, 30 with psychosis, and 42 with personality or adjustment disorder, compared to data of 134 healthy subjects, and evaluated in relation to gender, diagnosis, mode of attempt, and pharmacological treatment before attempt. The ratio leptin/BMI was used as a measure of adipocyte leptin secreting activity. RESULTS: Drugs taken for treatment before attempt, among them atypical neuroleptics, were not associated either to BMI or to plasma leptin. The positive correlation between BMI and leptin was significant in all groups. Compared to same gender controls, significant differences were found only for female patients, namely higher BMI for patients with psychosis and patients with bipolar disorder, while leptin/BMI ratio was higher only in females with bipolar disorder. CONCLUSION: BMI and plasma leptin in psychiatric suicide attempters are elevated in certain diagnostic groups in females, not related to previous pharmacologic treatment. The lack of a control group without a history of suicide attempts does not allow the attribution of enhanced leptin secreting activity found in female bipolar attempters specifically to suicidal behavior or to the disorder as a diagnostic entity.

Associations of plasma leptin to clinical manifestations in reproductive aged female patients with panic disorder.

Preclinical studies suggest the implication of the adipocyte hormone leptin in anxiety and fear processes. We explored for potential differences regarding plasma leptin, cortisol and the ratio leptin/Body Mass Index (BMI) between 27 medication-free female patients with Panic Disorder (PD) and 42 age-matched female controls, and for potential associations between plasma leptin and psychometric evaluations including number of panic attacks during last week, Clinical Global Impression-Severity of Illness (CGI-S) and Symptoms Checklist-90-Revised (SCL-90-R). Cortisol levels showed no differences between patients and controls, or correlations to leptin or to any clinical features. Both groups demonstrated a strong positive correlation between leptin and BMI and similar leptin and leptin/BMI, despite patients' lower BMI. However, patients -but not controls- demonstrated significant negative correlations of leptin to the 'somatization', 'anxiety', and 'phobic anxiety' SCL-90-R subscales. Moreover, there was a significant negative correlation of leptin and of leptin/BMI ratio to the number of panic attacks during last week, while higher CGI-S was associated with lower leptin/BMI ratio. Our results, limited to PD female patients, suggest that lower leptin serum levels are significantly associated with greater severity of psychopathological manifestations, including number of panic attacks, symptoms of somatization, anxiety and phobic anxiety and overall clinical presentation.

Psychoticism in patients with panic disorder with or without comorbid agoraphobia.

OBJECTIVE: A few case-reports have previously described transient psychotic-like symptoms in non-psychotic patients with panic disorder (PD). We aimed to systematically explore whether PD patients without any current or past psychosis can be differentiated according to the severity of 'psychoticism' as a dimension, comprising clinical features such as psychotic-like experiences, increased social alienation, hostility and suspiciousness. METHODS: Sample included 35 (female = 26) medication-free, non-psychotic patients consecutively referred from our Department's Outpatient Clinic for acute symptoms of DSM-5 PD with (PDA; N = 29) or without concurrent agoraphobia. Psychometric measures included the Symptom Checklist-90-Revised (SCL-90-R), Agoraphobic Cognitions Questionnaire (ACQ), Body Sensations Questionnaire (BSQ), and panic attacks during last 21 days PA-21d. RESULTS: Multiple regression analysis (forward stepwise) revealed that, among all SCL-90-R subscales, the psychoticism-subscale was most significantly associated with panic-related beliefs included in the ACQ, while significant associations emerged between the paranoid ideation-subscale and the ACQ and BSQ measures. Moreover, significant correlations emerged between the SCL-90-R psychoticism-subscale and all three measures of PD symptoms (ACQ, BSQ, PA-21d) and between the SCL-90-R paranoid ideation-subscale and both the ACQ and BSQ. CONCLUSIONS: This significant association between levels of psychoticism and severity of panic symptoms may reflect a more severe subtype of PD.

Association of Plasma Cortisol Levels with Clinical Characteristics of Suicide Attempters.

OBJECTIVE: There is evidence that suicidal behavior, among others, is an abnormal response to stress caused by a dysfunction in the activity of hypothalamus-pituitary-adrenal axis, and that cortisol levels are low in a considerable number of people attempting suicide. In this study, we aimed to search for associations of plasma cortisol levels with the clinical characteristics of a group of psychiatric suicide attempters. METHOD: The cortisol was measured in the morning in 200 psychiatric patients hospitalized after a suicide attempt, with diagnoses of major depressive disorder, bipolar disorder, psychosis, and personality/adjustment disorder, and compared to the levels of 138 healthy controls. Comparisons were also made for diagnostic subgroups and across diagnoses, with regard to depressive symptomatology, mode of attempt, suicide intent, number of attempts, and age. RESULTS: Cortisol levels were significantly lower for the whole group of attempters compared to controls. Furthermore, low cortisol levels characterized attempters with personality/adjustment disorder, higher depressive symptomatology, low suicide intent, non-violent attempt mode, repeated attempts, and of younger age. CONCLUSIONS: Certain clinical characteristics were identified in attempters with low cortisol levels. In previous studies, low cortisol levels have been associated with impairments in cognitive control, decision-making, and emotional processing that may lead, in the presence of stressors, to suicidal behavior, frequently with non-fatal outcome. Adding plasma cortisol levels to demographic and psychopathological data may help in identifying a subpopulation of attempters with neurocognitive deficits linked to dysfunction of Hypothalamic-Pituitary-Adrenal-axis activity, with implications for treatment.

Neurochemical and neuroendocrine correlates of overactive bladder at first demyelinating episode.

AIMS: Bladder dysfunction is frequent during the course of multiple sclerosis (MS), observed in up to 75% of patients. Urinary symptomatology can be a feature of the first episode of MS in a minority of cases, and most often shows characteristics of an overactive bladder (OAB), with voiding symptoms seen less frequently, often in combination with OAB. The neural control of micturition is complex, involving systems located in the brain, spinal cord, and periphery, and implicating central noradrenergic, serotonergic, and dopaminergic activities. Urinary disorders are also linked to anxiety and depression, conditions connected to hypothalamus-pituitary-adrenal axis activity. In this study we aimed to investigate neurochemical and neuroendocrine correlates of bladder dysfunction in early MS. METHODS: We included 101 patients at first demyelinating episode suggestive of MS that were drug-free at assessment. We evaluated the presence of urinary symptomatology and estimated CSF levels of the main metabolites of noradrenaline, serotonin, and dopamine, as well CSF-ACTH and serum cortisol. RESULTS: In total, 15 patients (15%) reported urinary dysfunction suggestive of OAB. Four of these had coexistent voiding symptomatology. The serotonin metabolite 5-HIAA was significantly reduced (P = 0.017) in patients with OAB syndrome, while there were no differences in the metabolites of noradrenaline (MHPG) and of dopamine (HVA). Additionally, significantly lower serum cortisol (P = 0.009) and borderline lower CSF-ACTH (P = 0.08) were found in patients with OAB. CONCLUSIONS: MS patients with OAB syndrome at the first demyelinating episode show reductions in central serotonergic activity and stress hormones. Whether the same changes persist at later disease stages remains to be investigated. Neurourol. Urodynam. 35:955-958, 2016. © 2015 Wiley Periodicals, Inc.

Lack of specific association between panicogenic properties of caffeine and HPA-axis activation. A placebo-controlled study of caffeine challenge in patients with panic disorder.

A subgroup of patients with Panic Disorder (PD) exhibits increased sensitivity to caffeine administration. However, the association between caffeine-induced panic attacks and post-caffeine hypothalamic-pituitary-adrenal (HPA)-axis activation in PD patients remains unclear. In a randomized, double-blind, cross-over experiment, 19 PD patients underwent a 400-mg caffeine-challenge and a placebo-challenge, both administered in the form of instant coffee. Plasma levels of adrenocorticotropic hormone (ACTH), cortisol and dehydroepiandrosterone sulfate (DHEAS) were assessed at both baseline and post-challenge. No patient panicked after placebo-challenge, while nine patients (47.3%) panicked after caffeine-challenge. Placebo administration did not result in any significant change in hormones' plasma levels. Overall, sample's patients demonstrated significant increases in ACTH, cortisol, and DHEAS plasma levels after caffeine administration. However, post-caffeine panickers and non-panickers did not differ with respect to the magnitude of the increases. Our results indicate that in PD patients, caffeine-induced panic attacks are not specifically associated with HPA-axis activation, as this is reflected in post-caffeine increases in ACTH, cortisol and DHEAS plasma levels, suggesting that caffeine-induced panic attacks in PD patients are not specifically mediated by the biological processes underlying fear or stress. More generally, our results add to the evidence that HPA-axis activation is not a specific characteristic of panic.

Serum leptin levels in treatment-naive patients with clinically isolated syndrome or relapsing-remitting multiple sclerosis.

Several studies have investigated leptin levels in patients with multiple sclerosis (MS) with somewhat conflicting results. They have all focused on patients with established relapsing-remitting (RR) MS but have not specifically looked at patients with clinically isolated syndrome (CIS) suggestive of MS, in the early stages of disease. In this study, serum leptin levels were measured in 89 treatment-naïve patients with CIS (53 patients) or RRMS (36 patients) and 73 controls searching for differences between the groups and for associations with several disease parameters. The expected significant sexual dimorphism in leptin levels (higher levels in females) was observed in both MS patients and controls. Increased leptin levels were found in female patients with RRMS compared to female controls (P = .003) and female CIS patients (P = .001). Female CIS patients had comparable levels to controls. Leptin levels correlated positively to disease duration, but not to EDSS, in female patients with RRMS. The results of the present study do not indicate involvement of leptin in the early stages of MS. Normal leptin levels in patients with CIS suggest that leptin does not have a pathogenic role. The ratio leptin/BMI increases during disease course in female MS patients in a time-dependent and disability-independent manner.

Testosterone and dehydroepiandrosterone sulfate in female anxious and non-anxious major depression.

OBJECTIVES: Major Depression with severe anxiety has been proposed as a distinct clinical variant of Major Depressive Disorder (MDD). This proposal invites the investigation of the differential biological correlates of the anxious versus non-anxious MDD. One such research area might be their possible differential associations with androgens. METHODS: Plasma total testosterone and dehydroepiandrosterone were assessed in adequately matched female inpatients with anxious MDD, non-anxious MDD and normal controls. RESULTS: Androgen levels were significantly lower in both patient groups compared to those of controls. Moreover, they were significantly lower in anxious MDD patients compared to those of their non-anxious MDD counterparts. The limitations of this study were cross-sectional design of the study, the small sample size of the study sample and the outpatient status of the control group. In addition, free testosterone levels were not measured. CONCLUSIONS: Our findings indicate that female major depression is associated with lower androgen levels, a deficiency aggravated by the severity of their concomitant anxiety.

Body Mass Index in Multiple Sclerosis: Associations with CSF Neurotransmitter Metabolite Levels.

Body weight and height of patients with relapsing-remitting multiple sclerosis (RRMS) or clinically isolated syndrome suggesting MS (CIS) in the age range 18 to 60 years (154 males and 315 females) were compared with those of subjects (146 males and 212 females) free of any major neurological disease. In drug-free patients, CSF levels of the metabolites of noradrenaline (MHPG), serotonin (5-HIAA), and dopamine (HVA), neurotransmitters involved in eating behavior, were estimated in searching for associations with body mass index (BMI). Statistical evaluations were done separately for males and females. Lower BMI was found in female MS patients compared to female controls, more pronounced in RRMS. BMI was not associated with duration of illness, smoking, present or previous drug treatment, or disability score. Body height showed a shift towards greater values in MS patients compared to controls. Patients in the lower BMI quartile (limits defined from control subjects) had lower 5-HIAA and HVA compared to patients in the upper quartile. The results provide evidence for weight reduction during disease process in MS, possibly related to deficits in serotoninergic and dopaminergic activities that develop during disease course, resulting in impairments in food reward capacity and in motivation to eat.

On the differential diagnosis of anxious from nonanxious major depression by means of the Hamilton Scales.

OBJECTIVE: Anxious major depressive disorder (A-MDD) is differentially diagnosed from nonanxious MDD (NA-MDD) as MDD with a cut-off score ≥ 7 on the HAM-D anxiety-somatization factor (ASF). We investigated whether additional HAM-D items discriminate A-MDD from NA-MDD. Moreover, we tested the validity of ASF criterion against HAM-A, gold standard of anxiety severity assessment. METHODS: 164 consecutive female middle-aged inpatients, diagnosed as A-MDD (n = 92) or NA-MDD (n = 72) by the normative HAM-A score for moderate-to-severe anxiety (≥ 25), were compared regarding 17-item HAM-D scores. The validity of ASF ≥ 7 criterion was assessed by receiver-operating characteristics (ROC) analysis. RESULTS: We found medium and large effect size differences between A-MDD and NA-MDD patients in only four out of the six ASF items, as well as in three further HAM-D items, namely, those of agitation, middle insomnia, and delayed insomnia. Furthermore, the ASF cut-off score ≥ 9 provided the optimal trade-off between sensitivity and specificity for the differential diagnosis between A-MDD and NA-MDD. CONCLUSION: Additional HAM-D items, beyond those of ASF, discriminate A-MDD from NA-MDD. The ASF ≥ 7 criterion inflates false positives. A cut-off point ≥ 9 provides the best trade-off between sensitivity and specificity of the ASF criterion, at least in female middle-aged inpatients.