Changes in the treatment of acute psychosis in a German public hospital from 1998 to 2004.

INTRODUCTION: The aim of our study was to investigate antipsychotic treatment strategies in acute schizophrenic episodes in a German university hospital. METHODS: Documented pharmacological procedures in the first six weeks of acute episodes of schizophrenia in the years 1998 (n = 108), 2001 (n = 92), and 2004 (n = 94) were analyzed. Inclusion criteria were: admission voluntary and involuntary as inpatient to our acute ward with a diagnosis of F20x according to ICD 10. RESULTS: Atypical antipsychotics (AAP) were significant more frequently used in the first week of treatment in 2001 and 2004 compared to the year 1998. Switching to AAP occurred significantly earlier in 2001 and 2004 (after 7.6 +/- 7 days in 1998, 3.5 +/- 5 days in 2001 and 2.3 +/- 5 days in 2004; P < 0.002). In all three years prescription of high potent typical antipsychotics decreased during the first six weeks of treatment. Involuntary treatment (P < 0.001) and age (P = 0.001) were significantly correlated to initial prescription of AAP. Involuntary admitted patients received more often a combination of high-potent conventional high potent typical neuroleptics and AAP (48% vs. 24%, P = 0.007). CONCLUSION: Second generation atypicals are used more frequently according to current guidelines and switching from conventional medications occurs earlier.

Neuropsychological assessment of adult patients with attention-deficit/hyperactivity disorder.

Adults with persistent attention-deficit/hyperactivity disorder (ADHD) may show cognitive deficits as compared to healthy control subjects. The aim of this study was to compare a sample of adult outpatients with ADHD on medication to healthy controls on a comprehensive neuropsychological assessment battery. Thirty adults with ADHD under stable psychopharmacological treatment and 27 healthy controls matched for age, gender, and IQ were assessed with ten tests measuring performance with regard to attention, memory, executive function, and fine motor control. Lower performance in patients as compared to controls was found in tests of verbal and visual memory, speed of visuo-motor search, set shifting, and divided attention. Indicators of response inhibition and simple response speed were less affected. Adults with ADHD show indicators of lowered cognitive performance under medication. These are related more to memory and attention under high mental load than to response inhibition or simple attention or motor performance.

Psychotropic drug prescription in a psychiatric university hospital in Germany.

A retrospective survey on drug prescription over a 5-year period (1998 to 2003) in 1,540 inpatients in a psychiatric university hospital in Germany was carried out. The aim was to establish a basis for a monitoring of prescription habits and for pharmacoeconomic considerations. It was established that there was only a slight increase in polyvalent drug use between 1998 and 2003. The results are presented in more detail in relation to the diagnosis of organic mental disorders, drug abuse disorders, schizophrenia, mood disorders and personality disorders. Newer atypical antipsychotics, SSRIs and mood stabilizers were increased across diagnoses while lithium and clozapine were prescribed less frequently. The rare occurrence of monotherapy in general might reflect a common trend in psychiatry fostering polydrug use. Studies of this type are biased by the fact that local habits of prescription do not allow generalisation of the findings. Such surveys should be carried out more frequently and simultaneously in different centers. Critical comparisons could help to optimize treatment.

A pilot clinical trial of oxcarbazepine in adults with attention-deficit hyperactivity disorder.

Despite the increasing recognition of attention-deficit hyperactivity disorder (ADHD) in adults, there is a paucity of controlled pharmacological trials. Recent reports have suggested the potential usefulness of mood stabilizing drugs for ADHD. To this end, the authors completed a pilot study with oxcarbazepine for the treatment of adults with ADHD. This was an open pilot study of oxcarbazepine (300-1,500 mg daily dosage) in adults who met DSM-IV criteria for ADHD. The treatment period was 8 weeks. Of the 9 subjects enrolled in the study (4 men, 5 women), 8 patients could be included in the analysis. At the endpoint of the active treatment, a significantly high proportion of subjects was considered improved while receiving oxcarbazepine. ADHD symptom checklist scores (ADHD-IV rating scale, Conners ADHD adult rating scale, ADHD self-rating [ADHD-SR] scale) showed significant reduction during the treatment period. Treatment with oxcarbazepine was relatively well tolerated; dizziness, sedation and nausea were the most frequently reported adverse effects. The results of this investigation indicate that oxcarbazepine may be a potentially useful agent for the treatment of ADHD in adults. However, placebo-controlled randomized trials are needed to provide evidence.

A rare case of dependence on pemoline.

This is the first case to report about a patient dependent on the dopaminergic CNS-stimulant pemoline. Throughout the treatment of adult attention-deficit hyperactivity disorder (ADHD) with pemoline mental (e.g. craving, loss of control) and physical symptoms (e.g. tolerance, withdrawal symptoms) appeared that fulfill the DSM-IV or ICD-10 criteria for dependence on psychostimulants. However, the dependence was regarded not to be induced by pemoline itself because the patient was prone to irregular and reinforced intake of amphetamines since her adolescence. Therefore, this case confirms the experience that in the treatment of ADHD the high risk to develop a dependence on psychostimulants is combined with a history of stimulant abuse.

Attention deficit hyperactivity disorder and borderline personality disorder.

To evaluate the association between attention deficit hyperactivity disorder (ADHD) and the diagnosis of borderline personality disorder (BPD) in adulthood, a systematic review of published follow-up data, mainly from observational studies was done. Electronic databases Medline, PsychInfo and PSYNDEXplus were searched from their earliest entries. All studies suggested significant relationships between ADHD and BPD. From a phenomenological point of view there seem to exist some similarities between these two disorders: deficits in affect regulation and impulse control, substance abuse, low self esteem and disturbed interpersonal relationship are common in both conditions. From a neuropsychological point of view dissociation in BPD might be regarded as a special form of behavioral inhibition and sustained attention comparable to ADHD. Possible therapeutic strategies of comorbid ADHD and BPD are discussed.

History of attention-deficit hyperactivity disorder symptoms and opioid dependence: a controlled study.

The co-occurrence of attention-deficit hyperactivity disorder (ADHD) and substance use disorders has received considerable attention in recent clinical and scientific investigations. These two disorders are linked to one another in a variety of ways. The core symptoms of ADHD may be mimicked by the effects of psychoactive substance use, making it difficult to diagnose one disorder in the presence of the other. Individuals with ADHD may demonstrate earlier onset of the substance abuse and a pattern of more frequent or intense use. ADHD symptoms were explored as possible antecedents of opioid dependence. A total of 109 adult opioid-dependent, treatment-seeking male and female outpatients were investigated with an extended clinical semistructured interview to collect sociodemographic, drug-related, and clinical data. The results indicate that ADHD alone does not predispose the development of opioid dependence in our sample. Childhood ADHD symptoms may nevertheless be found more frequently related to school performance problems and difficulties in social adaptation, which was identified in more than half of our population. Patients with ADHD history seemed to experience a drug abuse career with more complications which need to be recognized with focused attention in order to start earlier treatment strategies.

Antipsychotic treatment of psychosis associated with multiple sclerosis.

This case report deals with the antipsychotic treatment in multiple sclerosis (MS). Psychiatric symptoms are a frequent event in patients with MS. However, there are only few systematic studies of antipsychotic treatment in MS patients. Most of the studies are related to clozapine due to the lack of neurological, particularly extrapyramidal side effects (EPS). Therefore, experiences with other atypical drugs are requested. This paper discusses the pros and cons of different atypical drugs using the example of one patient, who showed adverse effects after treatment with quetiapine and olanzapine. Risperidone was not administered with respect to possible EPS. However, ziprasidone was tolerated well and appeared to be effective.

Buprenorphine in the treatment of opioid dependence.

Buprenorphine has become of increasing interest to be an alternative to methadone in the treatment of heroin addicts. The aim of the paper is to review, from a clinical perspective, the current status of what is known about the pharmacology of buprenorphine, with a particular emphasis on the issues of maintenance therapy in heroin addiction. A systematic review of published follow-up data, from observational and experimental studies was done. Electronic databases Medline and PSYNDEXplus were searched from their earliest entries. Buprenorphine appears to be a well-tolerated drug, with a benign overall side effect. Buprenorphine is an additional treatment option for heroin dependent patients, especially for those who do not wish to start or continue with methadone or for those who do not seem to benefit from adequate dosages of methadone.

[Descriptive analysis of drug-related deaths over a 5-year period]. / Deskriptive Analyse drogenassoziierter Todesfälle über einen 5-Jahres-Zeitraum.

OBJECTIVE: The purpose of the study was to examine opiate-related deaths in the German town Essen (inhabitants about 600,000) from 1990-1994. Sociodemographic data, psychiatric comorbidity and purity of the used opioids were of focussed interest. METHODS: 189 opiate-related deaths were analysed during the 5-year period. Patient files and police-related documents were used for the retrospective analysis. Purity of opioids was examined in a criminalistic laboratory and correlated with the number of deaths per time interval. RESULTS: The average age to start drug abuse in this cohort of 189 people was about 20, the average time of drug career was about 8.5 years, and the highest number of drug-related deaths was to be found at the age of 29-30. Purity of opioids was correlated statistically significantly (p < 0.05) with the number of deaths per period of time. CONCLUSIONS: After an average start of drug abuse at the age of 20 and a drug career of about a decade the risk of drug-related death seems to be relatively high at the age of about 30 years. Opiate purity seems to be relevant for drug-related death.

[Attention-deficit/hyperactivity disorder and substance abuse]. / Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung und Substanzmittelabhängigkeit.

Recent investigations of possible associations between attention deficit hyperactivity disorder (ADHD) and substance-use disorders are reviewed. ADHD seems to represent a possible risk factor for developing a substance abuse, up to 50% of patients with on continuing ADHD symptoms from childhood were found to develop a substance-use disorder. Based on possible pathophysiological similarities, especially cocaine and nicotine dependence are of focused interest in adolescents and adults with ADHD. The presence of ADHD may influence adolescent and adult substance-use disorders in different ways: earlier age of onset, higher frequency, longer duration of substance abuse and transition from alcohol-abuse to other substance-use disorders. Possible pharmacological and non-pharmacological therapeutic strategies in patients with ADHD and substance abuse are discussed.

Animal models of attention-deficit hyperactivity disorder.

Attention-deficit hyperactivity disorder (ADHD) involves clinically heterogeneous dysfunctions of sustained attention, with behavioral overactivity and impulsivity, of juvenile onset. Experimental models, in addition to mimicking syndromal features, should resemble the clinical condition in pathophysiology, and predict potential new treatments. One of the most extensively evaluated animal models of ADHD is the spontaneously hypertensive rat. Other models include additional genetic variants (dopamine transporter gene knock-out mouse, coloboma mouse, Naples hyperexcitable rat, acallosal mouse, hyposexual rat, and population-extreme rodents), neonatal lesioning of dopamine neurons with 6-hydroxydopamine, and exposure to other neurotoxins or hippocampal irradiation. None is fully comparable to clinical ADHD. The pathophysiology involved varies, including both deficient and excessive dopaminergic functioning, and probable involvement of other monoamine neurotransmitters. Improved models as well as further testing of their ability to predict treatment responses are required.

Subchronic haloperidol downregulates dopamine synthesis capacity in the brain of schizophrenic patients in vivo.

The antipsychotic effect of neuroleptics cannot be attributed entirely to acute blockade of postsynaptic D(2)-like dopamine (DA) receptors, but may arise in conjunction with the delayed depolarization block of the presynaptic neurons and reduced DA synthesis capacity. Whereas the phenomenon of depolarization block is well established in animals, it is unknown if a similar phenomenon occurs in humans treated with neuroleptics. We hypothesized that haloperidol treatment should result in decreased DA synthesis capacity. We used 6-[(18)F]fluoro-L-dopa (FDOPA) and positron emission tomography (PET) in conjunction with compartmental modeling to measure the relative activity of DOPA decarboxylase (DDC) (k(D)(3), min(-1)) in the brain of nine unmedicated patients with schizophrenia, first in the untreated condition and again after treatment with haloperidol. Patients were administered psychometric rating scales at baseline and after treatment. Consistent with our hypothesis, there was a 25% decrease in the magnitude of k(D)(3) in both caudate and putamen following 5 weeks of haloperidol therapy. In addition, the magnitudes of k(D)(3) in cerebral cortex and thalamus were also decreased. Psychopathology as measured with standard rating scales improved significantly in all patients. The decrease of k(D)(3) in the thalamus was highly significantly correlated with the improvement of negative symptoms. Subchronic treatment with haloperidol decreased the activity of DDC in the brain of patients with schizophrenia. This observation is consistent with the hypothesis that the antipsychotic effect of chronic neuroleptic treatment is associated with a decrease in DA synthesis, reflecting a depolarization block of presynaptic DA neurons. We link an alteration in cerebral catecholamine metabolism in human brain with the therapeutic action of neuroleptic medication.

Syndrome profiles in alcoholism and panic disorder with or without agoraphobia: an explorative family study.

It is proposed that alcoholism and panic disorder/agoraphobia demonstrate in part common genetic and environmental origins. Shared subthreshold symptom patterns in the parents' generation could confirm the proposed genetic role in alcoholism and panic disorder/agoraphobia, even if the parents do not fulfil the diagnostic criteria for a primary psychiatric diagnosis. This is the first family study of exploratively analyzing subthreshold symptoms in both disorders. The authors investigated families with panic disorder/agoraphobia and/or alcoholism with the Munich-Composite International Diagnostic Interview (M-CIDI). We documented the diagnoses according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria and subdivided the answers of the probands into 16 subthreshold diagnostic groups comprising 259 single items. We found statistically significant correlations of subthreshold syndrome profiles in the parents of patients with panic disorder/agoraphobia and alcoholism. The presented method of analyzing syndrome profiles in a family study seems to be a possibility to demonstrate references to genetic links between patients and parents in anxiety- and alcohol-related disorders.

Serotonin transporter binding increases in caudate-putamen and nucleus accumbens after neonatal 6-hydroxydopamine lesions in rats: implications for motor hyperactivity.

We examined serotonin (5-HT) transporters in rat forebrain using quantitative autoradiography at three distinct developmental stages after neonatal 6-hydroxydopamine lesions. The lesions substantially increased 5-HT transporter binding in both caudate-putamen and nucleus accumbens, but not cerebral cortex. The effects reached maximal levels as early as postnatal day (PD) 24, and were sustained until early adulthood. Behavioral analyses indicated that neonatal lesions resulted in motor hyperactivity on PD 24, but not on PD 36 or 59. These findings suggest that excess 5-HT transporters reflect serotonin hyperinnervation reported to occur in lesioned rats, and may modulate motor hyperactivity.

Organotypic rat cerebellar slice culture as a model to analyze the molecular pharmacology of GABAA receptors.

The preservation of the neuronal circuitry in rat cerebellar slice cultures provides an advantage in monitoring the development and characterizing the pharmacology of GABA(A) receptor subtypes. Sprague-Dawley rats, 8-11 days of age, were decapitated, their cerebella were cut into 400-microm slices and transferred into culture dishes. Cell viability and organotypic cerebellar organization of the culture remained well preserved up to 3 weeks. Autoradiographic procedures were introduced in these advanced culture technique and employed [(3)H]Ro 15-4513 in the absence and presence of 10 microM diazepam to visualize all benzodiazepine (BZD) and diazepam-insensitive (DIS) binding sites, respectively. Since expression of the alpha6 subunit variant of the GABA(A)/BZD receptor is restricted to the cerebellar granule cells and the BZD receptor agonist diazepam has very low affinity for this subunit, changes in DIS [(3)H]Ro 15-4513 binding sites during cultivation time can be attributed to changes in alpha6 subunit expression. A time-dependent development of total and DIS [(3)H]Ro 15-4513 binding sites were observed in the culture with a trend towards an increase in GABA(A) receptor alpha6 subunit levels during the first week. These findings suggest that explant preparations can be used to examine morphological changes in rat cerebellar slices. In addition, these preparations can be utilized to study the pharmacological effects of GABA(A)/BZD selective drugs on postnatal development of GABA(A) receptors in rat cerebellum.

Effects of norepinephrine and serotonin transporter inhibitors on hyperactivity induced by neonatal 6-hydroxydopamine lesioning in rats.

Consistent with their clinical effects in attention deficit-hyperactivity disorder (ADHD), the stimulants methylphenidate and amphetamine reduce motor hyperactivity in juvenile male rats with neonatal 6-hydroxydopamine (6-OHDA) lesions of the forebrain dopamine (DA) system. Since stimulants act on several aminergic neurotransmission systems, we investigated underlying mechanisms involved by comparing behavioral actions of d-methylphenidate, selective inhibitors of the neuronal transport of DA [GBR-12909 (1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-[3-phenylpropyl]piperazine dihydrochloride), amfonelic acid], serotonin [5-hydroxytryptamine (5-HT), citalopram, fluvoxamine], and norepinephrine (NE; desipramine, nisoxetine) in 6-OHDA lesioned rats. Selective dopamine lesions were made using 6-OHDA (100 microg, intracisternal) on postnatal day (PD) 5 after desipramine pretreatment (25 mg/kg, s.c.) to protect noradrenergic neurons. Rats were given test agents or vehicle, intraperitoneally, before recording motor activity for 90 min at PD 25 in a novel environment. d-Methylphenidate stimulated motor activity in sham controls and antagonized hyperactivity in lesioned rats. Selective DA transport inhibitors GBR-12909 and amfonelic acid greatly stimulated motor activity in sham control subjects, too, but did not antagonize hyperactivity in lesioned rats. In contrast, all selective 5-HT and NE transporter antagonists tested greatly reduced motor hyperactivity in 6-OHDA lesioned rats but did not alter motor activity in sham controls. The findings indicate that behavioral effects of stimulants in young rats with neonatal 6-OHDA lesions may be mediated by release of NE or 5-HT and support interest in using drugs that increase activity of norepinephrine or serotonin to treat ADHD.

Plasticity of dopamine D4 receptors in rat forebrain: temporal association with motor hyperactivity following neonatal 6-hydroxydopamine lesioning.

Genetic studies suggest that dopamine D(4) receptor polymorphism is associated with attention deficit hyperactivity disorder (ADHD). We recently reported that motor hyperactivity in juvenile male rats with neonatal 6-hydroxydopamine lesions of the central dopamine system can be reversed by dopamine D(4) receptor-selective antagonists. In this study, effects of such lesions on D(4) as well as other dopamine receptors (D(1) and D(2)) were autoradiographically quantified at selected developmental stages. Neonatal lesions resulted in motor hyperactivity at postnatal day (PD) 25, but not at PD 37 or 60. Correspondingly, D(4) receptor levels in lesioned rats were substantially increased in caudate-putamen and decreased in nucleus accumbens at PD 25, but not at PD 37 or 60. Neonatal lesions also led to relatively minor changes in D(1) and D(2) receptor binding in various forebrain regions. However, the time-course of lesion-induced motor hyperactivity correlated only with changes in D(4), but not D(1) and D(2) receptors. These results further support the hypothesis that D(4) receptors may play a pivotal role in lesion-induced hyperactivity, and possibly in clinical ADHD.

Effects of dopamine D4 receptor-selective antagonists on motor hyperactivity in rats with neonatal 6-hydroxydopamine lesions.

RATIONALE: Dopamine D4 receptor gene polymorphism has been repeatedly associated with attention deficit hyperactivity disorder (ADHD) and related personality traits. We recently reported that motor hyperactivity in an animal model of ADHD was dose-dependently reversed by CP-293,019, a D4 receptor-selective antagonist. However, behavioral effects of this agent may not be attributed exclusively to D4 receptor blockade, since it interacts with other sites including serotonin receptors. OBJECTIVES: To test further the hypothesis that D4 receptor blockade can reduce motor hyperactivity, behavioral effects of three chemically and pharmacologically dissimilar D4 antagonists were compared to that of ketanserin, a serotonin 5-HT(2A/2C) antagonist. METHODS: Selective dopamine lesions were made in male rats at postnatal day (PD) 5 with intracisternal 6-hydroxydopamine (100 microg) after desipramine pretreatment (25 mg/kg, SC) to protect noradrenergic neurons. Effects of D4 receptor-selective antagonists and ketanserin on lesion-induced motor hyperactivity were examined during the periadolescent period (postnatal days 23-26) with an infrared photobeam activity system. RESULTS: The D4 antagonists L-745,870 and U-101,958 dose-dependently inhibited motor hyperactivity in rats with neonatal lesions, whereas S-18126 lacked this effect at doses up to 30 mg/kg. None of these drugs affected motor behavior in sham control rats. In contrast, ketanserin produced apparent sedative effects in both lesioned and intact control rats without normalizing hyperactivity. CONCLUSIONS: Motor hyperactivity in this ADHD model was selectively antagonized by three of four dopamine D4 receptor antagonists evaluated, encouraging clinical assessment of D4 antagonists in patients with ADHD.