[Narcissistic personality disorder]. / Narzisstische Persönlichkeitsstörung.

Narcissism is a multifaceted term which encompasses traits of normal personality as well as a specific personality disorder. While much research has been concerned with narcissism as a trait there are only few empirical studies available on narcissistic personality disorder (NPS). The current diagnostic of NPS according to DSM-IV-TR focuses on grandiose type narcissism whereas vulnerable narcissism, which has been described by clinicians and researchers has not yet been recognised. Psychotherapy of narcissistic patients through different psychotherapeutic schools focuses mainly on processes in the therapeutic relationship, the analysis and change of grandiose and vulnerable schemas, emotion regulation techniques and correction of narcissistic behavior in favor of prosocial interactions.

Preliminary evidence of improvement of depressive symptoms but not impulsivity in cluster B personality disorder patients treated with quetiapine: an open label trial.

INTRODUCTION: Atypical antipsychotics might become a new treatment option for patients with an impaired impulse regulation as seen in cluster B personality disorders (PD). The aim of the present study is to investigate the efficacy and tolerability of quetiapine in patients with cluster B PD. METHODS: Fifteen in-patients with a DSM-IV diagnosis of borderline, histrionic, or narcissistic PD were treated for 8 weeks with quetiapine at a dose of 400 mg/day in an open-label fashion. Effects on impulsivity (Barratt Impulsiveness Scale, BIS), depressive symptoms (Hamilton Depression Scale, HAMD, and Beck Depression Inventory, BDI) and side effects (Dosage Record and Treatment Emergent Symptom Scale, DOTES) were assessed. RESULTS: Twelve patients completed the study. No positive effect on impulsivity (BIS) was found, but a significant improvement on depression scores (HAM-D and BDI) was noted. Adverse effects that might have been due to study medication were mainly anticholinergic and mild-to-moderate. DISCUSSION: The data of our preliminary open-label study do not argue for a general recommendation of quetiapine for the treatment of impulsivity in cluster B PD, but indicate positive effects on depressive symptoms.

[Psychopharmacologic treatment of personality disorders]. / Psychopharmakologische Behandlung von und bei Persönlichkeitsstörungen.

There is only a paucity of studies concerning the pharmacological treatment of personality disorders per se. On the other hand the clinical use of medication in these conditions is quite high, although there is no effective psychopharmacological treatment of distinct personality disorders. The psychopharmacological treatment of patients suffering from a personality disorder focuses on distinct symptoms and its comorbidity. Some symptoms could also be associated with other disorders like depression or psychosis, which often makes an exact differentiation of these disorders and a personality disorder difficult. Since symptoms of personality disorders are ego-syntonic, chronic and very often dependent on psychosocial factors, it is unlikely that a solely psychopharmacological treatment will be successful in most patients with a personality disorder. However, severe syndromes like depressive, impulsive, aggressive, dissociative, anxious or psychotic features may render a pharmacotherapy necessary. For the treatment of depressive syndromes or impulsivity a medical therapy with serotonin reuptake inhibitors, for the treatment of psychotic syndromes a medication with atypical antipsychotics is recommended. Impulsive or aggressive behaviour could be treated with mood stabilizers as well. Furthermore, there are indications for the use of alpha2-agonists, micro-opiate-antagonists and omega-3 fatty acid. The general use of benzodiazepines should be avoided as well as polypragmasy. Advantages versus potential damage of a high dose pharmacotherapy should be carefully weighed against each other. This article gives an overview over the today's most common psychopharmacological treatment possibilities in patients with a personality disorder.

Dissociative symptoms are positively related to stress in borderline personality disorder.

OBJECTIVE: According to DSM-IV criteria, dissociative symptoms in borderline personality disorder (BPD) occur in response to stress. Empirical evidence is, however, lacking. METHOD: Using ambulatory monitoring, we assessed dissociative symptoms and subjective ratings of stress every 60 min for 48 h on a palmtop computer in BPD-patients (n = 51), clinical controls (CC; major depression n = 25; panic disorder n = 26), and healthy controls (HC; n = 40). Data analyses were primarily based on hierarchical linear models. RESULTS: In all groups, states of increased stress were paralleled by increased scores of dissociation, thus confirming the hypothesized association between stress and dissociation. The increase in dissociation was more pronounced in BPD-patients when compared with CC and HC. Additionally, BPD-patients reported heightened dissociative experience compared with CC and HC, even after controlling for stress. CONCLUSION: Our data suggest that BPD-patients might be prone to dissociation when experiencing stress and are characterized by a generally heightened level of dissociation.

[Significance of emotion-focused concepts to cognitive-behavioral therapy]. / Bedeutung emotionsfokussierter Konzepte und Interventionen für die kognitive Verhaltenstherapie.

Emotions are the central process of motivation and play a key role in adaptive behavior in humans. Although cognitive-behavioral therapy stresses the importance of changing both cognition and behavior, there is growing emphasis on direct therapeutic work on emotions and emotional processing, as problematic emotional processes are at the core of nearly all psychic disorders. This type of work is the goal of emotion-focused psychotherapy, which centers on direct change of problematic emotions, especially those which are usually suppressed resp. overregulated by the patient. This paper examines the basic phobic/emotional conflict, the problematic emotional processes arising from this conflict, and the importance to cognitive-behavioral therapy of their potentially integrative role.

[Nacissistic personality disorder]. / Narzisstische Persönlichkeitsstörung. Immer Arger mit Mr. Bombastic.

The narcissistic personality disorder is the extreme form of the so-called narcissistic personality style, which is characterized by exaggerated self-importance coupled with an inordinate desire to be admired, ideas of grandiosity and a strong sense of entitlement, an absence of empathy and feelings of envy. In contact with others, the narcissist appears arrogant, readily feels injured, and takes advantage of other to achieve his own ends. A central psychodynamic role in the development of the condition is a labile sense of self-worth and its overcompensation. Psychotherapeutic treatment aims initially to develop an awareness of the problem in the patient, correction of cognitive dysfunction and a reduction in aggressive or disdainful behavior. Impulsive and aggressive behavior and attacks of depression may be reduced through the use of selective serotonin reuptake inhibitors.

Dopamine receptor regulating factor, DRRF: a zinc finger transcription factor.

Dopamine receptor genes are under complex transcription control, determining their unique regional distribution in the brain. We describe here a zinc finger type transcription factor, designated dopamine receptor regulating factor (DRRF), which binds to GC and GT boxes in the D1A and D2 dopamine receptor promoters and effectively displaces Sp1 and Sp3 from these sequences. Consequently, DRRF can modulate the activity of these dopamine receptor promoters. Highest DRRF mRNA levels are found in brain with a specific regional distribution including olfactory bulb and tubercle, nucleus accumbens, striatum, hippocampus, amygdala, and frontal cortex. Many of these brain regions also express abundant levels of various dopamine receptors. In vivo, DRRF itself can be regulated by manipulations of dopaminergic transmission. Mice treated with drugs that increase extracellular striatal dopamine levels (cocaine), block dopamine receptors (haloperidol), or destroy dopamine terminals (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) show significant alterations in DRRF mRNA. The latter observations provide a basis for dopamine receptor regulation after these manipulations. We conclude that DRRF is important for modulating dopaminergic transmission in the brain.

In situ hybridization on brain tissue.

ABSTRUCT: In situ hybridization (ISH) is an important method for determining the distribution of mRNA within cells or tissue preparations by hybridization of a nucleic acid probe (either DNA or RNA) with a specific target nucleic acid (usually mRNA) (1,2). Thus, ISH enables the localization of transcripts within cells, tissues, and whole body and allows a neuroanatomic comparison of specific mRNA expression with the respective protein expression. Furthermore, ISH can serve as a tool to detect quantitative changes in gene expression in distinct neuroanatomic areas under various experimental conditions.

Selective increase of dopamine D3 receptor gene expression as a common effect of chronic antidepressant treatments.

The mesolimbic dopaminergic system is a neuroanatomical key structure for reward and motivation upon which previous studies indicated that antidepressant drugs exert a stimulatory influence, via still unknown neurobiological mechanisms. Here we examined the effects of chronic administration of antidepressants of several classes (amitriptyline, desipramine, imipramine, fluoxetine and tranylcypromine) and repeated electroconvulsive shock treatments (ECT) on dopamine D3 receptor expression in the shell of the nucleus accumbens, a major projection area of the mesolimbic dopaminergic system. Short-term drug treatments had variable effects on D3 receptor mRNA expression. In contrast, treatments for 21 days (with all drugs except fluoxetine) significantly increased D3 receptor mRNA expression in the shell of nucleus accumbens; D3 receptor binding was also significantly increased by amitriptyline or fluoxetine after a 42-day treatment. ECT for 10 days increased D3 receptor mRNA and binding in the shell of nucleus accumbens. D1 receptor and D2 receptor mRNAs were increased by imipramine and amitriptyline, but not by the other treatments. The time-course of altered D3 receptor expression, in line with the delayed clinical efficiency of antidepressant treatment, and the fact that various antidepressant drugs and ECT treatments eventually produced the same effects, suggest that increased expression of the D3 receptor in the shell of nucleus accumbens is a common neurobiological mechanism of antidepressant treatments, resulting in enhanced responsiveness to the mesolimbic dopaminergic system.

In vivo regulation of glial cell line-derived neurotrophic factor-inducible transcription factor by kainic acid.

A putative transcription factor induced in vitro by glial cell line-derived neurotrophic factor (GDNF) and transforming growth factor-beta was recently cloned and characterized [Yajima S. et al. (1997) J. Neurosci. 17, 8657-8666]. The messenger RNA of this protein, termed murine GDNF-inducible transcription factor (mGIF, hereafter referred to as GIF), is localized within cortical and hippocampal regions of brain, suggesting that GIF might be regulated by perturbations of these brain regions. In an effort to learn more about the role of GIF in vivo, we examined GIF messenger RNA in the brains of rats treated with the glutamatergic agonist kainic acid. This treatment is known to induce seizures and alter the messenger RNA expression of several growth factors, including GDNF, in several brain regions. Rats were given intraperitoneal saline (1 ml/kg) or kainic acid (15 mg/kg) and were killed at various time-points for in situ hybridization of brain sections with a GIF messenger RNA riboprobe. In saline-treated rats, GIF messenger RNA was present at low levels in cerebral cortex, hippocampus and hippocampal remnants such as the taenia tecta. Kainic acid treatment induced robust increases in GIF messenger RNA in several brain regions, including cerebral cortex, hippocampus, caudate-putamen, nucleus accumbens, and several nuclei of the amygdala and hypothalamus. Most brain regions showed the greatest increase in GIF messenger RNA 4-6 h after kainic acid administration and a return towards normal levels at 48 h. The CA3 region of hippocampus, however, showed a more rapid increase in GIF messenger RNA that was also evident 48 h after kainic acid administration. These results demonstrate that GIF messenger RNA can be regulated in vivo, and that this novel factor warrants further study as a central mediator of GDNF and perhaps other neurotrophic factors.

Regulation of striatal dopamine receptors by estrogen.

The ability of estrogen to modulate the expression of ventral and dorsal striatal dopamine receptors D(1), D(2,) and D(3) was examined in vivo using semi-quantitative in situ hybridization and ligand binding autoradiography. Two-week treatment with subcutaneous pellets of 17beta-estradiol (25 mg) downregulated D(2) dopamine receptor mRNA in both dorsal and ventral striatum (shell and core regions of nucleus accumbens). No significant changes in D(1) or D(3) mRNA expression were detected. Ligand binding autoradiography did not reveal changes in D(1), D(2,) or D(3) receptor protein expression. We also assessed the ability of 17beta-estradiol to regulate D(2) gene promoter activity in NB41A3 neuroblastoma cells that express this gene endogenously using co-transfections with an estrogen receptor expression vector. While a small fragment of the D(2) promoter could be activated 2.5-fold by estrogen, a larger portion of the D(2) gene was not regulated by this treatment. Estrogens do not appear to have a net effect on striatal dopamine receptor expression. The observed downregulation of D(2) receptor mRNA in the dorsal and ventral striatum in vivo could be secondary to the increased striatal dopamine release induced by estrogen. Synapse 34:222-227, 1999. Published 1999 Wiley-Liss, Inc.

Regulation of striatal dopamine receptors by corticosterone: an in vivo and in vitro study.

The effects of chronic corticosterone administration and adrenalectomy on the expression of brain dopamine receptors were studied in rats. In situ hybridization and receptor binding autoradiography were carried out to determine D1, D2 and D3 receptor expression in dorsal and ventral striata. Except for down-regulation of D2 mRNA in dorsal striatum after 2 week corticosterone treatment, no other significant changes were detected. In addition, the transcriptional regulation of D1 and D2 gene promoters by glucocorticoids was studied in neuroblastoma cell lines using transient transfections. While a small segment of the D2-promoter could be activated three-fold by dexamethasone, large fragments of neither D1 or D2 promoters were regulated by this treatment. Glucocorticoids do not appear to have direct overall effects on striatal dopamine receptor expression. The observed down-regulation of D2 receptor mRNA in the dorsal striatum in vivo is likely secondary to increased striatal dopamine release induced by corticosterone.

Testosterone, gonadotropin, and cortisol secretion in male patients with major depression.

OBJECTIVE: Previous studies of sex hormone concentrations in depression yielded inconsistent results. However, the activation of the hypothalamic-pituitary-adrenal system seen in depression may negatively affect gonadal function at every level of regulation. The objective of this study was to explore whether major depressive episodes are indeed associated with an alteration of gonadal function. METHODS: Testosterone, pulsatile LH secretion, FSH, and cortisol were assessed using frequent sampling during a 24-hour period in 15 male inpatients with major depression of moderate to high severity and in 22 healthy comparison subjects (age range 22-85 years). RESULTS: An analysis of covariance model showed that after adjustment for age only, daytime testosterone (p < .01), nighttime testosterone (p < .05), and 24-hour mean testosterone secretion (p < .01) were significantly lower in the depressed male inpatients. There was also a trend for a decreased LH pulse frequency in the depressed patients (p < .08). CONCLUSIONS: Gonadal function may be disturbed in men with a depressive episode of moderate to high severity.

Coadministration of clozapine and fluvoxamine in psychotic patients--clinical experience.

Fluvoxamine (FLUVOX) is an inhibitor of the cytochrome P450 isoenzyme 1 A2 and thereby inhibits clozapine (CLOZ) metabolism. We performed an open clinical study to gather experience in necessary dosages, plasma levels, side effects and clinical efficiency of the coadministration of the two drugs. Eighteen psychotic patients were studied. 50 mg FLUVOX were given throughout the study period, while the CLOZ dosage was increased individually (week 5: 96.9+/-37.2 mg). After 5 weeks the plasma concentrations were as follows: CLOZ 252+/-174 ng/ml, N-desmethylclozapine (DM-CLOZ) 143+/-74 ng/ml and clozapine N-oxide (CLOZ N-OX) 30+/-14 ng/ml. There were no differences in side effects, especially sedation, after 5 weeks compared to the pretreatment condition. Moreover, we found a significant improvement in measures of cognitive speed which might be regarded as a measure of vigilance. The BPRS scores dropped continuously until week 5 (pretreatment: 53.3+/-13.4; week 5: 33.2+/-12.9) and 5 patients were considered treatment responders (BPRS reduction > 50%). Ten patients continued the combination treatment after the study period and 9 of these patients were in clinical remission when discharged. Given strict therapeutic drug monitoring, coadministration of FLUVOX and CLOZ seems to be a safe and efficient treatment strategy with a low occurrence of the side effects associated with CLOZ treatment. This might be due to additive effects of the two drugs and/or metabolic interaction.

PQBP-1, a novel polyglutamine tract-binding protein, inhibits transcription activation by Brn-2 and affects cell survival.

A novel gene, designated PQBP-1, which encodes a 265 residue protein that binds to the polyglutamine tract of the brain-specific transcription factor Brn-2, was identified. PQBP-1, which also interacts with the polyglutamine tract of triplet repeat disease gene products, binds with a higher affinity to an expanded polyglutamine tract. PQBP-1 has several functional domains, including hepta- and di-amino acid repeat sequences rich in polar residues essential for its interaction with the polyglutamine tract, a WWP/WW domain which binds to proline-rich motifs in other proteins, a putative nuclear localization signal sequence and a C2domain implicated in Ca2+-dependent phospholipid signaling. PQBP-1 is located in the nucleus and inhibits transcriptional activation by Brn-2. Overexpression of PQBP-1 in P19 embryonic carcinoma cells suppresses their growth rate and enhances their susceptibility to various stresses including serum deprivation, retinoic acid treatment and UV irradiation. Northern blot and in situ hybridization analyses revealed that PQBP-1 is a ubiquitous protein and is expressed primarily in neurons throughout the brain, with abundant levels in hippocampus, cerebellar cortex and olfactory bulb. These results suggest that PQBP-1 mediates important cellular functions under physiological and pathological conditions via its interaction with polyglutamine tracts.

Cerebrospinal fluid concentrations of corticotropin-releasing hormone, vasopressin, and somatostatin in depressed patients and healthy controls: response to amitriptyline treatment.

The effect of amitriptyline upon hypothalamic-pituitary-adrenal [HPA]-system-regulating neuropeptides (corticotropin-releasing hormone [CRH], vasopressin, somatostatin) was studied in a group of depressed elderly patients and controls. A first lumbar puncture was performed in 37 depressed in-patients. This was followed by a 6-week medication phase with amitriptyline. Upon its completion a second cerebrospinal fluid (CSF) sample was obtained in 18 of these 37 patients. In 25 healthy controls a first lumbar puncture was done eleven of these individuals agreed to take 75 mg/d amitriptyline for 6 weeks and to participate in the follow-up CSF study. Within the group of depressed patients amitriptyline led to a significant decrease of CSF CRH in treatment responders only (F1, 16 = 5.2; P < 0.02). Also, in normal controls CSF CRH concentration tended to decrease with amitriptyline treatment (t-test; P < 0.09). No effects of amitriptyline upon vasopressin or somatostatin were observed. In normal controls (r = 0.4; P < 0.02) and in patients (r = 0.4; P < 0.03) age correlated positively with baseline CSF somatostatin. A trend for CSF CRH to increase with aging was found only in controls (r = 0.3; P < 0.09); patients did not show a significant association here. Finally, CSF neuropeptide concentration at baseline did not differ between the group of depressed patients and healthy controls. Our study corroborates the evolving concept that antidepressants effect various components of the HPA system with the net result of a reduction in its activity. In addition, we found CSF CRH and CSF somatostatin concentrations to be better reflections of age than of depression and, finally, that during aging and during depression the HPA system changes in similar directions.

The combined dexamethasone/corticotropin-releasing hormone stimulation test is more closely associated with features of diurnal activity of the hypothalamo-pituitary-adrenocortical system than the dexamethasone suppression test.

BACKGROUND: The dexamethasone suppression test (DST) is a widely used endocrine test in psychiatry, but was reported to not allow reliable inferences with regard to the basal activity of the hypothalamo-pituitary-adrenocortical (HPA) system. We compared the association of the standard DST and the combined dexamethasone/corticotropin-releasing hormone (DEX/CRH) challenge with parameters of diurnal cortisol profiles. METHODS: We performed a DEX/CRH challenge and 24-hour cortisol profiles in 25 depressed patients (mean age: 47.4 +/- 16.0 years) and 33 age-matched healthy controls (mean age: 51.4 +/- 19.3 years). RESULTS: A path analysis showed cortisol area under the curve (AUC) after CRH (= DEX/CRH status) to be dependent upon minimal 24-hour cortisol and evening frequency of pulsatile cortisol release. In contrast, postdexamethasone cortisol (= DST status) was related to 24-hour mean cortisol. Simple linear regressions supported an association of cortisol AUC with several parameters of the diurnal cortisol profiles, which was not true for the standard DST. CONCLUSIONS: We conclude that the combined DEX/CRH challenge test is more closely associated with the activity of the HPA system than the standard DST in healthy and depressed subjects.

Cloning and characterization of murine glial cell-derived neurotrophic factor inducible transcription factor (MGIF).

The potent neurotrophic factor glial cell-derived neurotrophic factor (GDNF) is a distant member of the transforming growth factor-beta (TGF-beta) superfamily of proteins. We report a transcription factor that is the first nuclear protein known to be induced by GDNF, thus designated murine GDNF inducible factor (mGIF). The cDNA was cloned in the course of investigating transcription factors that bind to Sp1 consensus sequences, using the in situ filter detection method, and it was found to encode a protein having the same C2-H2 zinc finger motif as Sp1. Sequence analysis indicated that mGIF is homologous to the human TGF-beta inducible early gene (TIEG) and human early growth response gene-alpha (EGR-alpha). mGIF is widely distributed in the adult mouse with high mRNA levels in kidney, lung, brain, liver, heart, and testis. In the adult brain, mGIF is abundantly expressed in hippocampus, cerebral cortex, cerebellum, and amygdala with lower amounts in striatum, nucleus accumbens, olfactory tubercle, thalamus, and substantia nigra. During development, mGIF mRNA also has a wide distribution, including in cerebral cortex, cerebellar primordium, kidney, intestine, liver, and lung. GDNF induces the expression of mGIF rapidly and transiently both in a neuroblastoma cell line and in primary cultures of rat embryonic cortical neurons. Co-transfection of the Drosophila SL2 cells using mGIF expression plasmid and reporter constructs having Sp1 binding sites indicated that mGIF represses transcription from a TATA-containing as well as from a TATA-less promoter. These observations suggest that the zinc finger transcription factor mGIF could be important in mediating some of the biological effects of GDNF.