Ole Bernt Fasmer

FORMALIN TEST IN MICE, A USEFUL TECHNIQUE FOR EVALUATING MILD ANALGESICS

A modification of the formalin test appropriate for testing of mice is described. Formalin 1 or 5% was injected into the dorsal surface of a hindpaw, and the time the animal spent licking the paw was recorded. On the basis of the response pattern, two distinct periods of intensive licking activity were identified; an early (0-5 min after injection) and a late response (20-30 min after injection). The following analgesics were investigated (dose range): acetylsalicylic acid (100-400 mg/kg), paracetamol (100-400 mg/kg) and morphine (0.6-10 mg/kg). Acetylsalicylic acid (200-400 mg/kg early response, 300-400 mg/kg late response), paracetamol (200-400 mg/kg early response, 300-400 mg/kg late response) and morphine (2.5-10 mg/kg) inhibited the responses in a dose-dependent manner. The results indicate that the test is useful for evaluating mild analgesics. It may have advantages over some of the tests that are commonly used for testing analgesics.

Occupational Outcome in Adult ADHD: Impact of Symptom Profile, Comorbid Psychiatric Problems, and Treatment A Cross-Sectional Study of 414 Clinically Diagnosed Adult ADHD Patients

Objective: To determine the effects of symptom profile, comorbid psychiatric problems, and treatment on occupational outcome in adult ADHD patients. Method: Adult ADHD patients (N = 414) responded to questionnaires rating past and present symptoms of ADHD, comorbid conditions, treatment history, and work status. Results: Of the patients, 24% reported being in work, compared to 79% in a population-based control group (N = 359). Combined subtype of ADHD, substance abuse, and a reported history of depression or anxiety were correlated with being out of work. Current and past medical treatment of ADHD was correlated with being in work. Logistic regression analyses showed that stimulant therapy during childhood was the strongest predictor for being in work as adults (odds ratio = 3.2, p = .014). Conclusion: Early recognition and treatment of ADHD is a strong predictor of being in work as an adult, independently of comorbidity, substance abuse, and current treatment. (J. of Att. Dis. 2009; 13(2) 175-187)

Multicenter Analysis of the SLC6A3/DAT1 VNTR Haplotype in Persistent ADHD Suggests Differential Involvement of the Gene in Childhood and Persistent ADHD

Attention deficit/hyperactivity disorder (ADHD) is one of the most common neuropsychiatric disorders with a worldwide prevalence around 4–5% in children and 1–4% in adults. Although ADHD is highly heritable and familial risk may contribute most strongly to the persistent form of the disorder, there are few studies on the genetics of ADHD in adults. In this paper, we present the first results of the International Multicentre Persistent ADHD Genetics CollaboraTion (IMpACT) that has been set up with the goal of performing research into the genetics of persistent ADHD. In this study, we carried out a combined analysis as well as a meta-analysis of the association of the SLC6A3/DAT1 gene with persistent ADHD in 1440 patients and 1769 controls from IMpACT and an earlier report. DAT1, encoding the dopamine transporter, is one of the most frequently studied genes in ADHD, though results have been inconsistent. A variable number tandem repeat polymorphism (VNTR) in the 3′-untranslated region (UTR) of the gene and, more recently, a haplotype of this VNTR with another VNTR in intron 8 have been the target of most studies. Although the 10/10 genotype of the 3′-UTR VNTR and the 10-6 haplotype of the two VNTRs are thought to be risk factors for ADHD in children, we found the 9/9 genotype and the 9-6 haplotype associated with persistent ADHD. In conclusion, a differential association of DAT1 with ADHD in children and in adults might help explain the inconsistencies observed in earlier association studies. However, the data might also imply that DAT1 has a modulatory rather than causative role in ADHD.

Changes in nociception after lesions of descending serotonergic pathways induced with 5,6-dihydroxytryptamine: different effects in the formalin and tail-flick tests

Intrathecal administration of 5,6-dihydroxytryptamine (5,6-DHT) in mice selectively lesioned descending serotonergic pathways. Nociception was evaluated 3 days after injection of 5,6-DHT using the tail-flick and formalin tests. In the tail-flick test shortened latencies were found in the lesioned animals. In contrast, the initial behavioural response (0-15 min) to formalin was reduced, while the late response (15-40 min) was not altered. Fourteen days after intrathecal administration of 5,6-DHT the changes in nociception, both in the tail-flick and in the formalin test, had returned to the control level. These findings support the contention that the raphe-spinal serotonergic system participates in the tonic regulation of nociception in the spinal cord. Apparently this system tonically inhibits spinal nociceptive reflexes, but tonically enhances the initial behavioural responses to noxious chemical stimulation, as measured with the formalin test.

The prevalence of migraine in patients with bipolar and unipolar affective disorders

There is a well-known association between migraine and affective disorders, but the information is sparse concerning the prevalence of migraine in subgroups of the affective disorders. The present study was undertaken to investigate the prevalence of migraine in unipolar depressive, bipolar I and bipolar II disorders. Patients with major affective disorders (n = 62), consecutively admitted to an open psychiatric ward, were examined with a semi-structured interview based on DSM-IV diagnostic criteria, combined with separate criteria for affective temperaments. Diagnosis of unipolar and bipolar I disorders followed the DSM-IV criteria, while bipolar II disorder encompassed patients with either discrete hypomanic episodes or a cyclothymic temperament. Migraine was diagnosed according to IHS-criteria. Symptoms of migraine were found to be common in these patients, both in those with unipolar depression (46% prevalence of migraine) and in those with bipolar disorders (44% prevalence). Among the bipolar patients there was, however, a striking difference between the two diagnostic subgroups, with a prevalence of 77% in the bipolar II group compared with 14% in the bipolar I group (P = 0.001). These results support the contention that bipolar I and II are biologically separate disorders and point to the possibility of using the association of bipolar II disorder with migraine to study both the pathophysiology and the genetics of this affective disorder.

Acetylsalicylic acid, paracetamol and morphine inhibit behavioral responses to intrathecally administered substance P or capsaicin.

Intrathecally administered substance P (SP) or capsaicin in mice elicited a pain-related behavioral response consisting of vigorous biting, licking and scratching of the caudal part of the body. Pretreatment of the animals with intraperitoneally injected acetylsalicylic acid (300 and 400 mg/kg), paracetamol (300 and 400 mg/kg) and morphine (2.5 and 5 mg/kg) reduced the responses in a dose-dependent manner. The analgesia is probably mediated by inhibition of a postsynaptic SP sensitive mechanism. Thus these results demonstrate central antinociceptive effects of acetylsalicylic acid and paracetamol.

Migraine with and without aura: association with depression and anxiety disorder in a population-based study. The HUNT Study

Some data indicate that migraine with aura (MA) is more strongly associated with anxiety disorder and depression than migraine without aura (MoA), but the evidence is not conclusive. In the Nord-Trøndelag Health study 1995-1997, a total of 49 205 (75% of the participants) subjects gave valid answers to both HADS (Hospital Anxiety and Depression Scale) and a validated headache questionnaire. Associations between anxiety disorder/depression and MA/MoA were evaluated by multiple logistic regression analysis. Depression (DEP) [odds ratio (OR) 1.7; 95% confidence interval (CI) 1.2, 2.6] and depression with comorbid anxiety disorder (COM) (OR 1.6; 95% CI 1.2, 2.1) were more likely in women having MA than in those with MoA. No stronger association was found for pure anxiety disorder (ANX) in MA vs. MoA (OR 0.9; 95% CI 0.7, 1.5). Among men, we found no difference in prevalence of depression and anxiety disorders between MA and MoA. This is a new finding that might have relevance for both research and clinical treatment.

Clinical assessment and diagnosis of adults with attention-deficit/hyperactivity disorder

Attention-deficit/hyperactivity disorder (ADHD) is a prevalent disorder in adult psychiatry, particularly in out-patient settings. There are no objective, laboratory-based tests that can establish this diagnosis. Present diagnostic criteria for ADHD are formulated primarily according to behavior in childhood, based on age inappropriate and impairing levels of hyperactivity, impulsivity and inattention. Other symptoms, such as mood instability and frustration intolerance, are not included in current criteria for ADHD, but are very prevalent in this patient group. ADHD is often comorbid with alcohol and substance abuse and other psychiatric disorders, in particular anxiety and personality disorders. Thus, the diagnostic assessment should both include a comprehensive clinical interview, rating scales for past and present symptoms and collateral information from multiple informants, as well as assessment of a broader spectrum of psychiatric and somatic conditions. As ADHD is associated with changes in brain function mediating different aspects of neuropsychological functions, assessment of those functions is important to understand the symptom patterns and to develop targeted treatment programs. Some topics for further research and for future developments of diagnostic criteria and tools are highlighted.

Genetic Analyses of Dopamine Related Genes in Adult ADHD Patients Suggest an Association With the DRD5-Microsatellite Repeat, But Not With DRD4 or SLC6A3 VNTRs

Attention deficit hyperactivity disorder (ADHD) is a common and highly heritable psychiatric disorder in children and adults. Recent meta‐analyses have indicated an association between genes involved in dopaminergic signaling and childhood ADHD, but little is known about their possible role in adult ADHD. In this study of adults with ADHD, we evaluated the three most commonly studied ADHD candidate genetic polymorphisms; the dopamine receptor D4 (DRD4) exon 3 VNTR repeat, a microsatellite repeat 18.5 kb upstream of the DRD5 locus and the 3′UTR dopamine transporter SLC6A3 (DAT 1) VNTR. We examined 358 clinically diagnosed adult Norwegian ADHD patients (51% males) and 340 ethnically matched controls. We found a nominally significant overall association with adult ADHD for the DRD5 microsatellite marker (P = 0.04), and a trend toward increased risk associated with the 148‐bp allele consistent with recent meta‐analyses. The strongest overall association (P = 0.02) and increased risk for the 148‐bp allele [odds ratio (OR) = 1.27 (95% CI: 1.00–1.61)] were seen in the inattentive and combined inattentive/hyperactive group as previously reported for childhood ADHD. No association was found for the DRD4 or SLC6A3 polymorphisms in this patient sample. In conclusion, our results among adults with a clinical diagnosis of ADHD support an association between ADHD and the DRD5 locus, but not the DRD4 or SLC6A3 loci. It is possible that the latter polymorphisms are associated with a transient form of ADHD with better long‐term clinical outcome.

Time course of changes in nociception after 5,6-dihydroxytryptamine lesions of descending 5-HT pathways

Intrathecal injection of 5,6-dihydroxytryptamine (5,6-DHT) in rats produced selective lesions of the descending 5-HT pathways. Spinal 5-HT levels gradually fell to less than 10% of controls within 10 days of 5,6-DHT administration with no recovery evident within 4 weeks. The uptake of 14C-5-HT into crude spinal synaptosomes was similarly reduced. The uptake of 3H-NA into spinal synaptosomes was unaffected, as was the uptake of 14C-5-HT and 3H-NA into cortical synaptosomes. Following 5,6-DHT, tail-flick latencies were reduced by 20-30% during the first post-injection week, but returned to control levels during the second week. Intrathecal or systemic administration of the 5-HT receptor antagonist metergoline significantly reduced latencies of normal rats and of 5,6-DHT treated rats tested after the second week when the response was normalized. Metergoline did not, however, further reduce the latencies of lesioned rats during the first post-injection week. It is concluded that functional adaptation involving 5-HT neurotransmission compensated for the selective lesion of descending 5-HT pathways induced by 5,6-DHT.