[Pharmacotherapy of anxiety disorders-Guideline-conform treatment and new developments]. / Pharmakotherapie von Angsterkrankungen ­ leitliniengerechte Therapie und Neuentwicklungen.

Besides cognitive behavioral therapy (CBT), psychopharmacotherapy belongs to the first-line treatment approaches for anxiety disorders according to all national and international guidelines. According to studies and meta-analyses, modern antidepressants in particular have been proven to be effective. Depending on the substance, there are approvals for panic disorder, generalized anxiety disorder and social phobia. There are also approvals for other substance groups, e.g. anticonvulsants for generalized anxiety disorder. Benzodiazepines should be used with caution in view of the risk of dependency. Although effective and well-tolerated medications are available, up to 30% of patients still do not respond or do not respond adequately to treatment. Consequently, research efforts to develop new substances are important. Based on a better understanding of the complex neurobiological mechanisms underlying anxiety disorders, a large number of substances are currently undergoing clinical trials. Modulators of current and new transmitter systems, in particular the glutamatergic and the endocannabinoid systems as well as neuropeptides, are being discussed as innovative substances. Strategies are also being investigated which, in combination with psychotherapy, aim at optimizing fear extinction memory. First studies are also underway on the use of psychedelic agents in combination with psychotherapy for anxiety.

Grey matter structural differences in alcohol-dependent individuals with and without comorbid depression/anxiety-an MRI study.

Although depression and anxiety disorders are common comorbid conditions in alcohol dependence, few structural brain imaging studies have compared alcohol-dependent subjects with and without such comorbidity. In the current study, brain scans of 35 alcohol-dependent with and 40 individuals without diagnosis of a comorbid ICD-10 depressive or anxiety disorder receiving detoxification inpatient treatment were evaluated. Thickness and volumes of automatically segmented neuroanatomical structures were measured in FreeSurfer. Furthermore, associations of brain structure with biological markers and clinical severity markers of alcohol dependence were assessed. Despite comparable addiction severity, the non-comorbid group had evidence of higher cytotoxic effects of alcohol use on hepatic and haematological markers, and showed significantly smaller volumes of total cerebral, and cerebellar grey matter. Similarly, they showed unexpected smaller hippocampal and nucleus accumbens volumes, and thinner frontal, temporal and occipital cortices. Smaller brain volumes correlated with increased markers of hepatic and haematological dysfunction, and with longer duration of alcohol dependence in the non-comorbid group. Evidence of higher biomarkers of alcohol use may be indicative of more severe alcohol dependence or higher vulnerability to ethanol toxicity in this group. Furthermore, psychopathology-related drug treatment, which occurred in 53% of the comorbid group over the recent years, or tissue inflammation may have a moderate effect on the grade of cerebral atrophy in alcohol-dependent patients. Longitudinal studies are needed to investigate this issue more fully.

[Guideline-oriented inpatient psychiatric psychotherapeutic/psychosomatic treatment of anxiety disorders : How many personnel are need?]. / Leitliniengerechte stationäre psychiatrisch-psychotherapeutische/psychosomatische Behandlung von Angsterkrankungen : Wieviel Personal ist erforderlich?

BACKGROUND/OBJECTIVES: The reimbursement of inpatient psychiatric psychotherapeutic/psychosomatic hospital treatment in Germany is regulated by the German personnel ordinance for psychiatric hospitals (Psych-PV), which has remained unchanged since 1991. The aim of this article was to estimate the personnel requirements for guideline-adherent psychiatric psychotherapeutic hospital treatment. METHODS: A normative concept for the required psychotherapeutic "dose" for anxiety disorders was determined based on a literature review. The required staffing contingent was compared to the resources provided by the Psych-PV based on category A1. RESULTS: According to the German policy guidelines for outpatient psychotherapy, a quota of 25 sessions of 50 min each (as a rule plus 5 probatory sessions) is reimbursed. This approach is supported by studies on dose-response relationships. As patients undergoing inpatient treatment for anxiety disorders are usually more severely ill than outpatients, a contingent of 30 sessions for the average treatment duration of 5 weeks seems appropriate in order to fully exploit the costly inpatient treatment time (300 min per patient and week). In contrast, only 70 min are reimbursed according to the Psych-PV. The total personnel requirement for the normative concept is 624 min per patient and week. The Psych-PV only covers 488 min (78 %). CONCLUSION: Currently, the time contingents for evidence-based psychiatric psychotherapeutic/psychosomatic hospital care are nowhere near sufficient. In the development of future reimbursement systems this needs to be corrected.

Functional MRI activation in response to panic-specific, non-panic aversive, and neutral pictures in patients with panic disorder and healthy controls.

There is evidence that besides limbic brain structures, prefrontal and insular cortical activations and deactivations are involved in the pathophysiology of panic disorder. This study investigated activation response patterns to stimulation with individually selected panic-specific pictures in patients with panic disorder with agoraphobia (PDA) and healthy control subjects using functional magnetic resonance imaging (fMRI). Structures of interest were the prefrontal, cingulate, and insular cortex, and the amygdalo-hippocampal complex. Nineteen PDA subjects (10 females, 9 males) and 21 healthy matched controls were investigated using a Siemens 3-Tesla scanner. First, PDA subjects gave Self-Assessment Manikin (SAM) ratings on 120 pictures showing characteristic panic/agoraphobia situations, of which 20 pictures with the individually highest SAM ratings were selected. Twenty matched pictures showing aversive but not panic-specific stimuli and 80 neutral pictures from the International Affective Picture System were chosen for each subject as controls. Each picture was shown twice in each of four subsequent blocks. Anxiety and depression ratings were recorded before and after the experiment. Group comparisons revealed a significantly greater activation in PDA patients than control subjects in the insular cortices, left inferior frontal gyrus, dorsomedial prefrontal cortex, the left hippocampal formation, and left caudatum, when PA and N responses were compared. Comparisons for stimulation with unspecific aversive pictures showed activation of similar brain regions in both groups. Results indicate region-specific activations to panic-specific picture stimulation in PDA patients. They also imply dysfunctionality in the processing of interoceptive cues in PDA and the regulation of negative emotionality. Therefore, differences in the functional networks between PDA patients and control subjects should be further investigated.

[Social phobia]. / Soziale Phobie.

With a lifetime prevalence of 13% social phobia (social anxiety disorder) is a common and serious condition that should not be played down because of the burden associated with the disorder, an increased suicide rate and the frequent comorbidity with substance abuse disorders. Social phobia is characterized by the excessive and unrealistic fear of being scrutinized or criticized by others. The disorder often begins in adolescence.Symptoms of social phobia can be effectively treated with evidence-based treatment, including cognitive behavior therapy (CBT) and psychopharmacological medications. In the present paper, treatment recommendations are given, which are based on a systematic review of all available randomized trials for the treatment of social phobia. Among psychological therapies, variants of CBT have been proven to be effective in controlled studies. Selective serotonin reuptake inhibitors (SSRIs) and the selective serotonin norepinephrine reuptake inhibitor (SNRI) venlafaxine are among the drugs of first choice.

TMEM132D, a new candidate for anxiety phenotypes: evidence from human and mouse studies.

The lifetime prevalence of panic disorder (PD) is up to 4% worldwide and there is substantial evidence that genetic factors contribute to the development of PD. Single-nucleotide polymorphisms (SNPs) in TMEM132D, identified in a whole-genome association study (GWAS), were found to be associated with PD in three independent samples, with a two-SNP haplotype associated in each of three samples in the same direction, and with a P-value of 1.2e-7 in the combined sample (909 cases and 915 controls). Independent SNPs in this gene were also associated with the severity of anxiety symptoms in patients affected by PD or panic attacks as well as in patients suffering from unipolar depression. Risk genotypes for PD were associated with higher TMEM132D mRNA expression levels in the frontal cortex. In parallel, using a mouse model of extremes in trait anxiety, we could further show that anxiety-related behavior was positively correlated with Tmem132d mRNA expression in the anterior cingulate cortex, central to the processing of anxiety/fear-related stimuli, and that in this animal model a Tmem132d SNP is associated with anxiety-related behavior in an F2 panel. TMEM132D may thus be an important new candidate gene for PD as well as more generally for anxiety-related behavior.

Neuropeptide S receptor gene -- converging evidence for a role in panic disorder.

Animal studies have suggested neuropeptide S (NPS) and its receptor (NPSR) to be involved in the pathogenesis of anxiety-related behavior. In this study, a multilevel approach was applied to further elucidate the role of NPS in the etiology of human anxiety. The functional NPSR A/T (Asn¹°7Ile) variant (rs324981) was investigated for association with (1) panic disorder with and without agoraphobia in two large, independent case-control studies, (2) dimensional anxiety traits, (3) autonomic arousal level during a behavioral avoidance test and (4) brain activation correlates of anxiety-related emotional processing in panic disorder. The more active NPSR rs324981 T allele was found to be associated with panic disorder in the female subgroup of patients in both samples as well as in a meta-analytic approach. The T risk allele was further related to elevated anxiety sensitivity, increased heart rate and higher symptom reports during a behavioral avoidance test as well as decreased activity in the dorsolateral prefrontal, lateral orbitofrontal and anterior cingulate cortex during processing of fearful faces in patients with panic disorder. The present results provide converging evidence for a female-dominant role of NPSR gene variation in panic disorder potentially through heightened autonomic arousal and distorted processing of anxiety-relevant emotional stimuli.

Nocturnal urinary cortisol excretion over a randomized controlled trial with paroxetine vs. placebo combined with relaxation training or aerobic exercise in panic disorder.

INTRODUCTION: Data on basal hypothalamo-pituitary-adrenomedullary (HPA) function over controlled treatment trials with serotonergic drugs in anxiety disorders are still rare. METHODS: 29 patients with panic disorder participating in a 10 week randomized, controlled trial (paroxetine vs. placebo with exercise or relaxation; N=60) collected urine for cortisol excretion over 3 consecutive nights before start and before termination of the treatment episode. Urinary cortisol was measured by radioimmunoassay. Efficacy measures were the Clinical Global Impression Scale (CGI) and the Panic and Agoraphobia Scale (P&A). 83% were female (p<.05 vs. males). 55% received additional aerobic exercise, and 45% relaxation. 55% received paroxetine treatment, and 45% placebo. Significantly fewer males received placebo treatment (p<.05). RESULTS: All subjects improved significantly. Cortisol excretion did not differ between treatment groups or at pre-/post measurements. Females showed a significantly higher variability of cortisol excretion compared to males, at pre-(p<.005) and post (p=.015) assessments. Males displayed a trend to lower basal HPA function at end of treatment (p=.08). HPA variability after treatment showed a trend to be higher in the paroxetine (p=.052) -who clinically improved significantly better- compared to the placebo group. No relationship between HPA activity and treatment response or with exercise was detected. DISCUSSION: HPA function shows significant gender differences, with females having a higher HPA function variability. Future studies on HPA function in treatment trials should address gender and medication effects.

[Early detection of anxiety disorders]. / Depressive Verstimmung, Vermeidungsverhalten, Alkoholprobleme. Steckt eine Angststörung dahinter?

Anxiety disorders represent a widespread illness. Those affected with initial symptoms usually seek the help of their family doctor. In many cases, considerable time passes before the diagnosis has been established and specialised treatment applied, with the result that chronification is furthered. Physical symptoms of an anxiety disorder, and fears of contracting somatic disease are almost always the first to be described. In patients abusing alcohol and/or hypnotics consideration must always be given to an anxiety disorder. Previously existing symptoms almost always include depressive moods or avoidance behavior. Stressful life events and other psychosocial stressful factors may also point the way to the early diagnosis of an anxiety disorder.

Improvement of quality of life in panic disorder with escitalopram, citalopram, or placebo.

BACKGROUND: It has been argued that measurement of outcome in panic disorder should not be limited to monitoring the number of panic attacks, but should include all domains that affect patient quality of life. METHODS: Data from a randomized prospective comparison of escitalopram, citalopram, and placebo in patients with DSM-IV panic disorder were analyzed with regard to measurements of impairment of quality of life. The subscales of the Panic and Agoraphobia Scale (P&A) (Panic Attacks, Agoraphobic Avoidance, Anticipatory Anxiety, Functional and Social Disability, and Worries about Health) and the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) were analyzed. RESULTS: Treatment with escitalopram was associated with significant improvement on all 5 subscales of the P&A. Citalopram was significantly different from placebo in 3 subscales. Escitalopram and citalopram were significantly better than placebo in improving quality of life (measured by the total score of the Q-LES-Q Scale). Escitalopram was superior to placebo on 12 of 16 items of the Q-LES-Q, while citalopram was superior on 7 items. CONCLUSION: The P&A scale was more robust than measurement of panic frequency in differentiating medication from placebo. Escitalopram treatment was associated with improvement on all assessed domains that impair quality of life in panic disorder. Measurement of clinical improvement should not be solely based on panic attack frequency, but should also include assessment of a broad range of domains that affect patient quality of life.

Rgs 2 gene polymorphisms as modulators of anxiety in humans?

Rgs2 (regulator of G-protein signalling 2) gene recently was reported as a quantitative trait gene for anxious behaviour in mice and male Rgs2 knockout mice have been shown to be more anxious than wildtype mice. Therefore we investigated four non-coding single nucleotide polymorphisms in a sample of 173 patients with panic disorder and 173 matched controls of German descent. At the genotype level all four SNPs were associated with panic disorder (p = 0.02-0.05). At the haplotype level the strongest association was observed for a haplotype containing SNP3 and SNP 4 (subgroup men and men with agoraphobia: p = 0.01 and 0.03). This points towards a functional polymorphism at the 3' end of the gene. Our results support the hypothesis that variations of the Rgs2 gene play a role also for the development of anxiety in humans.

[Not Available]. / Wie lange muss mindestens behandelt werden?

Anxiety disorders show a tendency to become chronic. Behavioral treatment and pharmacotherapeutic measures must frequently be applied over a lengthy period of time. The most suitable drugs for long-term treatment are the selective serotonin reuptake inhibitors (SSRI) and the serotonin norepinephrine reuptake inhibitor (SNRI), venlafaxine. With regard to side effects, the specific characteristics of the anti-anxiety drugs used for long-term therapy must be taken into account.

[The alpha2delta subunit of the voltage-dependent calcium channel. A new pharmaceutical target for psychiatry and neurology]. / Die alpha2delta-Untereinheit der spannungsabhängigen Kalziumkanäle Ein neues pharmakologisches Ziel in der Psychiatrie und Neurologie.

Calcium channel blockers are substances used for treating high blood pressure and coronary heart disease. New medications have been developed that modulate calcium channels but also show promise in psychiatric and neurologic applications. Gabapentin and pregabalin bind to a subunit of calcium channels--the alpha2delta receptors--thereby reducing calcium influx to neurons. As a result, less glutamate is released from nerve endings that use excitatory amino acids as transmitters. This in turn reduces substance P-related activation of AMPA heteroreceptors on noradrenergic synapses, total transmitter release, and finally neuronal activity. That mechanism is the probable explanation for gabapentin's and pregabalin's usefulness in the treatment of neuropathic pain but also their possible anticonvulsive and anxiolytic effects.

[Pharmacotherapy in personality disorders]. / Pharmakotherapie bei Persönlichkeitsstörungen.

Subjects with personality disorders represent a relevant subset of the clinical psychiatric population and, to an even bigger extent, a comorbid condition to an axis-I diagnosis. Personality disorders appear to be difficult to treat and problematic in the therapeutic setting, and a pharmacologic treatment often does not follow recommendations from empirical studies. Psychopharmacologic drugs are able to modify the expression of certain personality dimensions, which are mainly disorder-related variables of temperament. Modern pharmacotherapy of personality disorders has a neurobiological basis. This is underlined by evidence from animal studies and can be associated with certain receptor-specific functions in humans. Treatment is consequently symptom-related and not specific for any disorder. It must be stressed that certain features but not the entire personality can be modified by drug treatment. Data from drug studies are still relatively scarce. An overview of studies on personality disorders is presented including information on dosages and augmenting strategies. Psychotherapy still is the basic treatment for personality disorders. However, psychopharmacological interventions should not only be considered when psychotherapy has failed. Treatments should be complementary from the start. There is a rationale for short- and long-term treatment. The latter is indicated, despite of the scarcity of data, when longer lasting and severe affective symptoms emerge. Response rates vary among the trials and appear to be lower than in non-comorbid axis-I disorders. A treatment algorithm is presented.

Randomized, double-blind study of SR142801 (Osanetant). A novel neurokinin-3 (NK3) receptor antagonist in panic disorder with pre- and posttreatment cholecystokinin tetrapeptide (CCK-4) challenges.

OBJECTIVE: The present study was designed to examine the efficacy and tolerability of the non-peptide neurokinin-3 (NK3) receptor antagonist SR142801 in outpatients suffering from panic disorder. METHODS: In a pilot study, 52 patients who were responders to a cholecystokinin tetrapeptide (CCK-4) challenge were randomized to four weeks of treatment with SR142801 (n = 36) or placebo (n = 16). Panic symptoms were assessed on weekly visits and a second CCK-4 challenge was performed at the end of the double-blind placebo controlled treatment period. Tolerability of SR142801 was generally good. RESULTS: The proportion of patients who had at least one adverse event (AE) in the SR142801 group and the placebo group was similar (58.3 and 50 %, respectively). Independent of treatment group, patients' overall panic symptomatology was substantially improved at the end of the treatment. CONCLUSION: With regard to efficacy of outcome, the compound was not significantly different from placebo. However, post-CCK-4 plasma prolactin concentrations showed a significant difference between placebo and SR142801.