Clozapine for the treatment of aggressiveness and agitation in advanced dementia.

BACKGROUND: Distressing behavioural symptoms, particularly agitation and aggressiveness, remain a difficult problem in everyday clinical practice in the treatment of multimorbid patients with dementia. Clozapine may be an effective therapeutic alternative in this context. METHODS: In a retrospective study, patients who had a diagnosis of dementia and had been treated in a specialized geriatric psychiatry unit with clozapine between August 2018 and February 2022 were included, and medical records were systematically reviewed. The Clinical Global Impressions Scale was used to assess improvement, and the Pittsburgh Agitation Scale for symptom reduction. In addition, side effects and clinical features were documented in detail. RESULTS: A total of 31 patients (median age 82 years) were identified with a mean clozapine dose of 47.2 (SD 35.6) mg. A total of 13 patients tolerated clozapine very well, 10 showed tolerable side effects, and in 10 patients side effects were the reason for stopping clozapine. Behavioural symptoms improved significantly, as indicated by the assessment scores. CONCLUSIONS: In summary, clozapine was effective and well tolerated in 23 patients, suggesting that low-dose clozapine may help to alleviate the suffering of difficult-to-treat multimorbid patients with advanced dementia and their caregivers. However, particular attention should be paid to adverse drug reactions, especially in patients with cardiovascular and pulmonary impairment.

Development of novel biological resection criteria for safe and oncologically satisfying resection of hepatocellular carcinoma.

OBJECTIVE: To develop criteria for safe and oncologically satisfying liver resection in case of early hepatocellular carcinoma with a 5-year overall survival (OS) similar to liver transplantation. SUMMARY BACKGROUND DATA: Liver resection (LR) and liver transplantation (LT) are potentially curative treatment options for hepatocellular carcinoma. Generally, LT achieves better OS. Due to organ shortage, however not all patients can receive a LT. METHODS: To decide which patients to resect and which to transplant we have developed biological resection criteria (BRC) as a compound out of mGPS (modified Glascow Prognostic Scale) and the Kings-Score (for HCV cirrhosis). These are based on routine clinical values that reflect both liver function and tumor biology/immunology. RESULTS: 276 patients were analyzed. Patients undergoing LR within BRC (inBRC) had a significantly better overall (73.6% vs. 35.4%, (p < 0.001)) and disease-free survival (54.7% vs. 17.2%, (p < 0.001)) as compared to patients outside the BRC (outBRC). The predictive value of BRC was independent of tumor burden. In a subgroup analysis outBRC patients had significantly worse outcome after major resection. In LT patients BRC had no predictive value. CONCLUSIONS: BRC may be a valuable tool to predict survival after LR for HCC. Patients resected inBRC may achieve comparable survival as LT. LR in outBRC patients are unlikely to be curative. All outBRC patients should be monitored closely for salvage LT.

Age-based seizure threshold determination.

OBJECTIVE: The intent was to improve seizure threshold titration by decreasing stimuli number. METHOD: An age-based method of titration for initial seizure threshold bilateral electroconvulsive therapy was constructed and used in 15 women and 9 men aged 35 to 80 years. Titration steps were one eighth, one fourth, three eighths, one half, five eighths, three fourths, 1, and 1.2 times age, expressed as "% Energy." RESULTS: Male thresholds were a significantly (P < 0.05, t(22) = 2.18) higher percentage of age (61.9%; SD, 32.6%) than female thresholds (41.2%; SD, 15.2%). Four women (27%) and 4 men (44%) showed seizure thresholds more than 50% of age. On average, women received 3.2 stimuli and men received 4.4 stimuli. No patient seized at one-eighth age. All patients who seized at one-fourth age were women and younger than 65 years. CONCLUSIONS: For women younger than 65 years, these data suggest that titration starting at one-fourth age should require 1.8 stimuli on average. For older women, starting at three-eighths age should average 1.8 stimuli. For men, starting at three-eighths age should require 2.4 stimuli, but with steps at three fourths, 1, and 1.25 age titration should average 1.8 stimuli. Age-based dosing should succeed in women younger than 65 years at one-half age and older than 65 years at five-eighths age. For men, dosing at one-half age should succeed among one half and is a reasonable initial titration dose.

Electroconvulsive therapy exerts mainly acute molecular changes in serum of major depressive disorder patients.

Electroconvulsive therapy (ECT) is mainly used to treat medication resistant major depressive disorder (MDD) patients, with a remission rate of up to 90%. However, little is known about the serum molecular changes induced by this treatment. Understanding the mechanisms of action of ECT at the molecular level could lead to identification of response markers and potential new drug targets for more effective antidepressant treatments. We have carried out a pilot study which analysed serum samples of MDD patients who received a series of ECT treatments over 4 weeks. Patients received only ECT treatments over the first two weeks and a combination of ECT and antidepressant drugs (AD) over the subsequent two weeks. Blood serum analyses were carried out using a combination of multiplex Human MAP® immunoassay and liquid-chromatography mass spectrometry (LC-MS(E)) profiling. This showed that ECT had a predominant acute effect on the levels of serum proteins and small molecules, with changes at the beginning of ECT treatment and after administration of the ECT+AD combination treatment. This suggested a positive interaction between the two types of treatment. Changed molecules included BDNF, CD40L, IL-8, IL-13, EGF, IGF-1, pancreatic polypeptide, SCF, sortilin-1 and others which have already been implicated in MDD pathophysiology. We conclude that ECT appears to exert mainly acute effects on serum molecules.

ECT stimulus dose dependence on current separately from charge.

Bilateral electroconvulsive therapy (ECT) seizure threshold charge averaged 162.8 and 125.1 mC at 900 and 1150 mA, respectively (p<0.02), measured in randomized balanced order (N=18). Results are consistent with stimulus dose strongly depending on current besides charge, rather than charge alone. ECT stimuli of differing currents but equal charge differ in dose.

Proteomic changes induced by anaesthesia and muscle relaxant treatment prior to electroconvulsive therapy.

PURPOSE: Electroconvulsive therapy (ECT) is a psychiatric treatment in which seizures are electrically induced in patients. Prior to treatment, patients are usually given short-acting anaesthetics and muscle relaxants to avoid harm, e.g. musculoskeletal injury, during the convulsions. However, most molecular studies investigating the mechanism of action of ECT have not explored the potential effects of the pre-treatment with anaesthetic and/ or muscle relaxant. EXPERIMENTAL DESIGN: We have carried out a targeted proteome analysis using multiplex immunoassay platform of serum samples before and 10 min after initiating the administration of the anaesthetic methohexital(®) and the muscle relaxant succinylcholine(®) to eight major depressive disorder patients undergoing ECT. RESULTS: Twenty-six out of 142 analysed molecules showed significant differences in abundance after the methohexital/succinylcholine treatment. Importantly, eight of these molecules (fatty acid-binding protein, insulin, interleukin (IL)1ß, IL-10, IL-4, prolactin, S100 calcium-binding protein B and tumor necrosis factor α) have been associated previously with effects of ECT. CONCLUSIONS AND CLINICAL RELEVANCE: These findings indicate that caution should be used when interpreting results in existing and future proteome-based biomarkers studies on the effects of ECT in neuropsychiatric disease or the use of anaesthetic/muscle relaxant in major surgical operations related to different therapeutic areas.

Altered auditory processing in patients with panic disorder: a pilot study.

OBJECTIVES: Clinical and electrophysiological studies suggest that panic disorder (PD) patients show disturbed response inhibition to sensory stimuli. Thus, habituation of neuronal activation after repeated sine tone stimulation was assessed by functional magnetic resonance imaging (fMRI) in patients with PD. METHODS: Twenty patients with PD and 20 age- and gender-matched healthy controls were assessed by 3T fMRI for auditory habituation. During three stimulation cycles of digitally generated pulsed (ν=5 Hz) 800-Hz sine tones alternating with silent periods, activation of the auditory cortex and other anxiety- or sensory integration-related regions was assessed. Brain activation was further analyzed dependent on functional serotonin transporter (5-HTT) gene variation (5-HTTLPR). RESULTS: PD patients demonstrated an extended brain activity in the first stimulation block, which normalized during the second stimulation cycle. A positive correlation with anxiety measures (HAMA) and an increased activity of distinct anxiety- or sensory integration-related areas (e.g., BA 22, BA 10) were seen during the third block of auditory stimulation. There was a significant interaction of left amygdala activation and the 5-HTTLPR S allele. CONCLUSIONS: Our results support the hypothesis of an aberrant processing of sensory information in PD patients. This phenomenon may underlie an enhanced responsiveness to anxiety-relevant or irrelevant stimuli possibly increasing PD vulnerability.

Elevated metabolites within dorsolateral prefrontal cortex in rapid cycling bipolar disorder.

Metabolites within the left dorsolateral prefrontal cortex (DLPFC) of six inpatients with bipolar II rapid cycling (RC) during various mood states (depressed, hypomanic, and euthymic), six depressed inpatients with non-RC bipolar disorder (BIPD), and six healthy controls (HC) were assessed by proton magnetic resonance spectroscopy (MRS). We hypothesized that glutamate/glutamine levels should be altered in RC compared with HC. Patients with RC in contrast to BIPD and HC exhibited elevated levels of N-acetylaspartate (NAA), choline (Cho), creatine (Cr), and glutamate/glutamine (Glx) during all mood states. The Glx levels of BIPD compared with HC did not differ significantly; the other metabolites were increased, though less than in RC patients. Our findings of elevated metabolites in patients with RC, especially Glx as a possible marker of cortical activity, indicate that increased neuronal activity may constitute an important neurobiological feature of RC.

Auditory processing of sine tones before, during and after ECT in depressed patients by fMRI.

Our goal was to assess treatment effects of electroconvulsive therapy (ECT) on acoustic processing in major depression. We hypothesized that (1) depression is related to functional alterations in auditory networks, and that (2) pre-treatment alterations in auditory networks are reversible through treatment with ECT. Acoustic perception of 20 severely depressed and 20 age and gender matched healthy controls was investigated by 3 T functional magnetic resonance imaging employing repeated stimulation by sine tones. Prior to ECT, depressed patients presented a multimodal recruitment of additional brain areas including regions of the secondary visual system (cuneus, lingualis) and the medial frontal cortex. During ECT, signal intensities were reduced compared to pre-ECT values and controls. Activation of several regions increased after ECT. Our data suggest that depression is accompanied by cortical dysfunction including impaired auditory processing of non-speech stimuli. This might be based on overall alterations of brain metabolism indicating functional impairment.

Memory performance in severely depressed patients treated by electroconvulsive therapy.

OBJECTIVES: Depression is accompanied by disturbed implicit (unconscious) and explicit (conscious) memory functions. The aim was the assessment of immediate and delayed verbal and visual memory functions, concentration/attention during the course of electroconvulsive therapy (ECT) treatment. METHODS: Twenty severely depressed, drug-treatment resistant, elderly patients were assessed with the Wechsler Memory Scale-Revised (WMS-R) before and at the end of the ECT series. RESULTS: Patients revealed deficits in acquisition (immediate verbal and visual memory), attention/concentration, and retrieval of information (delayed memory) before ECT. After ECT, significant improvements were observed in immediate memory but not in delayed memory. Although higher total stimulation levels (millicoulombs) (P = 0.015) were associated with improvements in immediate visual memory, we found that longer duration of convulsions (P = 0.016) as well as lower levels of stimulation at last ECT (P = 0.036) were associated with improvements in immediate verbal memory. Moreover, we found that stimulation energy (millicoulombs) in total and at last ECT was the best predictor among several clinical and ECT parameters of improved visual memory and concentration and decreased verbal and general memory. CONCLUSIONS: Prefrontal cortex-related memory processes, especially immediate memory encoding, improved after ECT, whereas long-term memory remained impaired, indicating that severely depressed patients remain cognitively inferior to normal subjects despite clinically successful treatment. This study may yield a better understanding of the time course of memory alterations in severely depressed patients receiving ECT. Improvement of immediate memory may be essential for establishing normal daily activities of life in the recovery phase of depression.

The neurochemical basis of human cortical auditory processing: combining proton magnetic resonance spectroscopy and magnetoencephalography.

BACKGROUND: A combination of magnetoencephalography and proton magnetic resonance spectroscopy was used to correlate the electrophysiology of rapid auditory processing and the neurochemistry of the auditory cortex in 15 healthy adults. To assess rapid auditory processing in the left auditory cortex, the amplitude and decrement of the N1m peak, the major component of the late auditory evoked response, were measured during rapidly successive presentation of acoustic stimuli. We tested the hypothesis that: (i) the amplitude of the N1m response and (ii) its decrement during rapid stimulation are associated with the cortical neurochemistry as determined by proton magnetic resonance spectroscopy. RESULTS: Our results demonstrated a significant association between the concentrations of N-acetylaspartate, a marker of neuronal integrity, and the amplitudes of individual N1m responses. In addition, the concentrations of choline-containing compounds, representing the functional integrity of membranes, were significantly associated with N1m amplitudes. No significant association was found between the concentrations of the glutamate/glutamine pool and the amplitudes of the first N1m. No significant associations were seen between the decrement of the N1m (the relative amplitude of the second N1m peak) and the concentrations of N-acetylaspartate, choline-containing compounds, or the glutamate/glutamine pool. However, there was a trend for higher glutamate/glutamine concentrations in individuals with higher relative N1m amplitude. CONCLUSION: These results suggest that neuronal and membrane functions are important for rapid auditory processing. This investigation provides a first link between the electrophysiology, as recorded by magnetoencephalography, and the neurochemistry, as assessed by proton magnetic resonance spectroscopy, of the auditory cortex.

fMRI studies of sensitivity and habituation effects within the auditory cortex at 1.5 T and 3 T.

PURPOSE: To assess habituation effects in relation to field strength by fMRI at 1.5 vs. 3.0 T within the auditory cortex of healthy subjects. MATERIALS AND METHODS: fMRI experiments were performed on 19 healthy subjects at 1.5 T (N = 12) and 3 T (N = 12). The auditory cortex was stimulated binaurally by digitally generated pulsed (nu = 5 Hz) 800 Hz sine tones with three alternating on and off periods. RESULTS: The mean activation after stimulation (4.4% +/- 1.2% (1.5 T) and 5.3% +/- 2.3% (3 T)) and number of activated pixels (96.7 +/- 49.8 (1.5 T) and 139.9 +/- 101 (3 T)) were higher at 3 T compared to 1.5 T; however, that difference did not reach statistical significance. A characteristic signal decay with repeated stimuli was revealed at both 1.5 and 3 T, and the response to the second and third stimulation blocks was significantly lower compared to the first. The habituation pattern was the same, independently of field strength and age. CONCLUSION: The mean activation and number of pixels were only modestly higher at 3 T, probably due to higher physiologic noise and higher local macroscopic susceptibility gradients within the temporal lobes at 3 T. Our data reveal that measured auditory habituation is independent of field strength, and data obtained at two different field strengths do not differ fundamentally in this context.

Effects of antidepressive therapy on auditory processing in severely depressed patients: a combined MRS and MEG study.

BACKGROUND: Alterations in brain metabolism as well as in brain function in different brain areas can be observed in severely depressed patients. METHODS: The present study combined proton magnetic resonance spectroscopy (1H MRS, n=16; healthy controls n=27) and magnetoencephalography (MEG, n=17, controls n=18) of the left auditory cortex in severely depressed inpatients pre- and post successful antidepressive therapy. For MEG recordings, patients were stimulated with trains of 4 successive vowels or 4 sine tones, respectively. For each of the 4 stimuli, the amplitude and latency of the N1m was calculated. As a measure of habituation the decrease of the individual amplitudes of the second, third and fourth N1m compared to the first N1m was calculated. RESULTS: Prior to therapy, a subset of patients presented clearly disturbed auditory processing to stimuli (missing of distinct N1m1 and subsequent habituation; 5 of 17 patients (vowels) and 9/17 (tones, respectively)). After treatment, compared to controls, a normalized habituation pattern was observed in all patients for vowels, but not for tones. In contrast, MRS revealed no significant differences between the metabolite concentrations of patients and healthy controls in both measurements. CONCLUSION: Depression may be accompanied by impaired auditory processing, which seems to improve with reduction in depressive symptoms. Auditory cortical dysfunction probably reflects only a part from more widespread aberrations of brain function occurring with severe mood disorder.

Serial proton spectroscopy in a case of adult-onset subacute sclerosing panencephalitis.

A case of subacute sclerosing panencephalitis in a 27-year-old man was serially evaluated with proton magnetic resonance spectroscopy. Metabolic abnormalities included decreased N-acetylaspartate and elevated choline and myo-inositol in a lesion visible on magnetic resonance imaging and in normal-appearing white matter. Lactate appeared increased within the lesion. Metabolic impairment was persistent after intrathecal interferon-alpha treatment. Spectroscopy pointing to ongoing inflammation, gliosis, and possible membrane turnover was more sensitive than imaging in detecting widespread pathology within the white matter.

Studies on a German (Münster) version of the temperament auto-questionnaire TEMPS-A: construction and validation of the briefTEMPS-M.

BACKGROUND: Based on classic German concepts of a continuum between depressive, hyperthymic, cyclothymic, and irritable temperaments and affective disorder (and adding an anxious type to the four), Akiskal and co-workers developed the Temperament Evaluation of Memphis, Pisa, Paris and San Diego both in interview (TEMPS-I) and auto-questionnaire (TEMPS-A) versions. It is the aim of the present analyses to validate a brief German version of TEMPS-A. METHODS: A total of 1056 students of the Westfalische-Wilhelms-Universitat in Munster, Germany, filled out the long 110-item version of the TEMPS-A (Munster translation by Erfurth: TEMPS-M) modified into a five gradation Likert format and with the items randomized. Based on this data we constructed a brief version of the TEMPS-M. In a second study, a sample of 151 students were recruited who filled out the briefTEMPS-M twice, approximately 1 month apart. RESULTS: Our psychometric procedures resulted in the retention of 35 items from the original 110. The proposed five-factor structure of the original TEMPS-A was upheld, with relatively few item reclassification (mainly due to some overlap between depressive and anxious traits). Internal consistency (Cronbach alpha values ranging from 0.69 to 0.84) and test-retest reliability were shown. Most importantly, all temperaments in the briefTEMPS-M correlated quite well (Pearson r values ranging from 0.49 to 0.72) with their respective original versions in the longer TEMPS-M. As for construct validity, significant correlation was shown with the Beck Depression Inventory for all but the hyperthymic temperament; the hyperthymic, cyclothymic and irritable correlated highest with the self-report Manic Inventory. LIMITATIONS: The study sample of university students was selective. CONCLUSIONS: We were able to construct a brief German version of the TEMPS-A auto-questionnaire. We submit this shorter version will be suitable for both clinical (psychiatric and general medical) and neurobiological research, as well as in studies on temperament features in selected populations, e.g., allowing comparisons between regions or different (German-speaking) countries.

Distribution and gender effects of the subscales of a German version of the temperament autoquestionnaire briefTEMPS-M in a university student population.

BACKGROUND: This paper examines the distribution of the temperamental characteristics and gender effects of a new autoquestionnaire developed by Akiskal et al. (TEMPS-A) in its German briefTEMPS-M version. METHODS: As described in a companion article [J. Affect. Disord. 85 (2005), 53, this issue], based on a study population of 1056 students of the Westfälische-Wilhelms-Universität in Münster, Germany, we constructed the briefTEMPS-M. In the present paper we report on the basic descriptive statistics of the five subscales of the briefTEMPS (depressive, cyclothymic, hyperthymic, irritable, and anxious), as well as gender differences. RESULTS: Except for the hyperthymic, these subscales are capable of representing the full range of temperament in a sample of German students. Characteristics of the distribution (skewness, kurtosis) of the subscales are well in acceptable limits. We found higher depressive, cyclothymic, and anxious, as well as lower hyperthymic, temperament values in women as compared to men. Cut-off scores to determine extreme groups are provided. To render our results comparable to a similar study using the interview version of the TEMPS-I in an Italian student population [J. Affect. Disord. 47 (1998) 1; J. Affect. Disord. 51 (1998) 7], we computed the rates for dominant temperaments based on the z scores +2 S.D., and obtained the following: depressive, 4.7%; cyclothymic, 4.7%; hyperthymic, 2.1%; irritable, 4.0%; and anxious, 4.2%. CONCLUSIONS: The briefTEMPS-M is a potentially valuable scale to quickly assess temperament in research, clinical and normal samples.

Basal prolactin values correlate with response to reboxetine treatment in major depression, but not with response to citalopram.

Little is known about variables that might predict outcome in major depression. Recently, basal prolactin values (BPV) have been suggested to predict response to treatment with tricyclic antidepressive drugs. In order to examine whether BPV predict response to selective mono-aminergic therapy, 24 in-patients with major depression were treated in a single-masked, randomised study using the most selective noradrenergic or serotonergic reuptake inhibitors available for antidepressant treatment, i.e. reboxetine and citalopram. A significant correlation between BPV and treatment response to reboxetine was found, but not between BPV and response to citalopram. As BPV are influenced by noradrenergic activity, it can be hypothesized that depressed patients with comparatively high BPV have a relatively high noradrenergic function. This might explain why in our study depressed patients with the highest BPV responded strongest to selective noradrenergic treatment with reboxetine. As measurement of BPV is simple, further studies are suggested to examine the possible clinical value of the link between prolactin, noradrenergic function in major depression and treatment response.

Treatment of bipolar mania with right prefrontal rapid transcranial magnetic stimulation.

BACKGROUND: Transcranial magnetic stimulation (TMS) has been suggested for the treatment of a variety of CNS disorders including depression and mania. METHODS: Nine bipolar (I) in-patients diagnosed with mania were treated with right prefrontal rapid TMS in an open and prospective study. Eight of nine patients received TMS as add-on treatment to an insufficient or only partially effective drug therapy. RESULTS: During the 4 weeks of TMS treatment a sustained reduction of manic symptoms as measured by the Bech-Rafaelsen mania scale (BRMAS) was observed in all patients. LIMITATIONS: Due to the open and add-on design of the study, a clear causal relationship between TMS treatment and reduction of manic symptoms cannot be established. CONCLUSIONS: Our data suggest that right prefrontal rapid TMS is safe and efficacious in the add-on treatment of bipolar mania showing laterality opposed to the proposed effect of rapid TMS in depression.