Nils Lindefors

Effectiveness of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: an open randomised clinical trial

BACKGROUND Second-generation antipsychotic drugs were introduced over a decade ago for the treatment of schizophrenia; however, their purported clinical effectiveness compared with first-generation antipsychotic drugs is still debated. We aimed to compare the effectiveness of second-generation antipsychotic drugs with that of a low dose of haloperidol, in first-episode schizophrenia. METHODS We did an open randomised controlled trial of haloperidol versus second-generation antipsychotic drugs in 50 sites, in 14 countries. Eligible patients were aged 18-40 years, and met diagnostic criteria for schizophrenia, schizophreniform disorder, or schizoaffective disorder. 498 patients were randomly assigned by a web-based online system to haloperidol (1-4 mg per day; n=103), amisulpride (200-800 mg per day; n=104), olanzapine (5-20 mg per day; n=105), quetiapine (200-750 mg per day; n=104), or ziprasidone (40-160 mg per day; n=82); follow-up was at 1 year. The primary outcome measure was all-cause treatment discontinuation. Patients and their treating physicians were not blinded to the assigned treatment. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN68736636. FINDINGS The number of patients who discontinued treatment for any cause within 12 months was 63 (Kaplan-Meier estimate 72%) for haloperidol, 32 (40%) for amisulpride, 30 (33%) for olanzapine, 51 (53%) for quetiapine, and 31 (45%) for ziprasidone. Comparisons with haloperidol showed lower risks for any-cause discontinuation with amisulpride (hazard ratio [HR] 0.37, [95% CI 0.24-0.57]), olanzapine (HR 0.28 [0.18-0.43]), quetiapine (HR 0.52 [0.35-0.76]), and ziprasidone (HR 0.51 [0.32-0.81]). However, symptom reductions were virtually the same in all the groups, at around 60%. INTERPRETATION This pragmatic trial suggests that clinically meaningful antipsychotic treatment of first-episode of schizophrenia is achievable, for at least 1 year. However, we cannot conclude that second-generation drugs are more efficacious than is haloperidol, since discontinuation rates are not necessarily consistent with symptomatic improvement.

Increased expression of brain-derived neurotrophic factor mRNA in rat hippocampus is associated with improved spatial memory and enriched environment

Enriched environment has been shown to enhance learning and memory and to induce morphological changes in the hippocampus. We report that rats housed in an enriched environment showed improved performance in the Morris water maze and decreased spontaneous motor activity. Exposure to behavioural tests increased expression of the mRNA that encodes brain-derived neurotrophic factor in the hippocampus. This was not seen when rats subjected to impoverished housing were tested suggesting that environmental history of the animal is of importance to induce expression of brain-derived neurotrophic factor in the hippocampus that may promote neuronal changes related to learning and memory.

Cognitive behavior therapy via the Internet: a systematic review of applications, clinical efficacy and cost–effectiveness

Internet-based cognitive behavior therapy (ICBT) is a promising treatment that may increase availability of cognitive behavior therapy (CBT) for psychiatric disorders and other clinical problems. The main objective of this study was to determine the applications, clinical efficacy and cost–effectiveness of ICBT. The authors conducted a systematic review to identify randomized controlled trials investigating CBT delivered via the internet for adult patient populations. Searches to identify studies investigating cost–effectiveness of ICBT were also conducted. Evidence status for each clinical application was determined using the American Psychologist Association criteria for empirically supported treatments. Of 1104 studies reviewed, 108 met criteria for inclusion, of which 103 reported on clinical efficacy and eight on cost–effectiveness. Results showed that ICBT has been tested for 25 different clinical disorders, whereas most randomized controlled trials have been aimed at depression, anxiety disorders and chronic pain. Internet-based treatments for depression, social phobia and panic disorder were classified as well-established, that is, meeting the highest level of criteria for evidence. Effect sizes were large in the treatment of depression, anxiety disorders, severe health anxiety, irritable bowel syndrome, female sexual dysfunction, eating disorders, cannabis use and pathological gambling. For other clinical problems, effect sizes were small to moderate. Comparison to conventional CBT showed that ICBT produces equivalent effects. Cost–effectiveness data were relatively scarce but suggested that ICBT has more than 50% probability of being cost effective compared with no treatment or to conventional CBT when willingness to pay for an additional improvement is zero. Although ICBT is a promising treatment option for several disorders, it can only be regarded as a well-established treatment for depression, panic disorder and social phobia. It seems that ICBT is as effective as conventional CBT for respective clinical disorder, that is, if conventional CBT works then ICBT works. The large effects and the limited therapist time required suggest that the treatment is highly cost effective for well-established indications.

Hippocampal damage and kainic acid injection induce a rapid increase in mRNA for BDNF and NGF in the rat brain

In situ hybridization and Northern blots were used to study expression of mRNAs for members of the nerve growth factor family in the rat brain following an excitatory stimulus. One hour after a unilateral needle insertion or saline injection into the dorsal hippocampus, the level of brain-derived neurotrophic factor (BDNF) mRNA increased markedly in granular neurons of the dentate gyrus and in the piriform cortex ipsilateral to the injection. The same treatment also increased the level of NGF mRNA in granular neurons of the ipsilateral dentate gyrus. The rapid increase in BDNF and NGF mRNA after a needle insertion or injection of saline was transient and preceded by an increase in c-fos mRNA in the same brain regions. In contrast to a needle insertion per se or a saline injection, 7 h after a unilateral injection of kainic acid into the dorsal hippocampus, the level of BDNF mRNA was dramatically increased in the ipsilateral hippocampus, as well as in the ipsilateral frontoparietal, piriform and perihinal cortex, the amygdaloid complex, claustrum, and ventromedial hypothalamus. A less pronounced increase was also seen in these brain areas on the contralateral side. Northern blots revealed that the level of BDNF mRNA increased 5- and 40-fold in the contra- and ipsilateral hippocampus, respectively, compared to sham-operated control animals. In contrast to BDNF and NGF, the level of hippocampus-derived neurotrophic factor/neurotrohin-3 (HDNF/NT-3) mRNA was not altered by either needle insertion or injection of saline or kainic acid.(ABSTRACT TRUNCATED AT 250 WORDS)

Tachykinin multiplicity in rat central nervous system as studied using antisera raised against substance P and neurokinin A

Antisera were raised in rabbits against the tachykinins neurokinin A (NKA) and substance P (SP). All NKA-antisera tested cross-reacted markedly with NKB, kassinin and eledoisin in radioimmunoassay (RIA), but virtually not with SP and physalaemin. Also when used for immunohistochemistry, one of the NKA-antisera was found to be virtually without cross-reactivity with SP. The most specific SP-antiserum did not cross-react with NKA but to some extent with NKB at the immunohistochemical level. Using these two antisera, the same distribution pattern of immunoreactivity was seen in both the rat substantia nigra and dorsal spinal cord. In neutral extracts of the substantia nigra, all NKA-antisera used for RIA detected a major component which eluted at the position of NKA in reverse phase high performance liquid chromatography, while no or only little immunoreactivity was detected at the position of NKB. A major component of substance P-like immunoreactivity (SPLI) co-eluting with SP and one or two minor SPLI-components were also detected in these extracts. An SP-antiserum, which cross-reacted markedly with physalaemin, detected an additional rather prominent component. In neutral water extracts of dorsal spinal cord the component detected with the NKA-antisera at the position of NKB, as well as one of the SPLI-components not eluting in the position of SP, were much more prominent than in the corresponding extracts of substantia nigra. In acetic acid extracts of both tissues, only one major SPLI-component co-eluting with SP could be detected, while only very small amounts of immunoreactivity eluting at the position of NKA and NKB (dorsal spinal cord only) could be detected using the NKA-antisera. The present results illustrate the importance of the extraction method used in immunochemical studies and demonstrate that the relative proportions of various tachykinins are markedly different in the rat substantia nigra and dorsal spinal cord.

Cognitive Effects of Antipsychotic Drugs in First-Episode Schizophrenia and Schizophreniform Disorder: A Randomized, Open-Label Clinical Trial (EUFEST)

OBJECTIVE Cognitive impairment, manifested as mild to moderate deviations from psychometric norms, is present in many but not all schizophrenia patients. The purpose of the present study was to compare the effect of haloperidol with that of second-generation antipsychotic drugs on the cognitive performance of patients with schizophreniform disorder or first-episode schizophrenia. METHODS Subjects were 498 patients with schizophreniform disorder or first-episode schizophrenia who were randomly assigned to open-label haloperidol (1 to 4 mg/day [N=103]), amisulpride (200 to 800 mg/day [N=104]), olanzapine (5 to 20 mg/day [N=105]), quetiapine (200 to 750 mg/day [N=104]), or ziprasidone (40 to 160 mg/day [N=82]). The Rey Auditory Verbal Learning Test, Trail Making Test Part A and Part B, WAIS Digit Symbol Test, and Purdue Pegboard Test were administered at baseline and the 6-month follow-up evaluation. RESULTS Compared with scores at baseline, composite cognitive test scores improved for all five treatment groups at the 6-month follow-up evaluation. However, there were no overall differences among the treatment groups. In addition, there was a weak correlation between the degree of cognitive improvement and changes in Positive and Negative Syndrome Scale scores. CONCLUSION Treatment with antipsychotic medication is associated with moderate improvement in the cognitive test performance of patients who have schizophreniform disorder or who are in their first episode of schizophrenia. The magnitude of improvement does not differ between treatment with haloperidol and treatment with second-generation antipsychotics. Moreover, cognitive improvement is weakly related to symptom change.

Internet administration of self-report measures commonly used in research on social anxiety disorder: A psychometric evaluation

The Internet has become increasingly popular as a way to administer self-report questionnaires, especially in the field of Internet delivered psychological treatments. Collecting questionnaire data over the Internet has advantages, such as ease of administration, and automated scoring. However, psychometric properties cannot be assumed to be identical to the paper-and-pencil versions. The aim of this study was to test the equivalence of paper-and-pencil and Internet administered versions of self-report questionnaires used in social phobia research. We analyzed data from two trials in which samples were recruited in a similar manner. One sample (N=64) completed the paper-and-pencil version of questionnaires and the second sample (N=57) completed the same measures online. We included the Liebowitz Social Anxiety Scale-self-assessment (LSAS-SR), the Social Interaction and Anxiety Scale (SIAS), and the Social Phobia Scale (SPS) as measures of social anxiety. Also included were the Montgomery Asberg Depression Rating Scale-self-assessment (MADRS-S), the Beck Anxiety Inventory (BAI), and the Quality of Life Inventory (QOLI). Results showed equivalent psychometric properties across administration formats. Cronbachs @a ranged between 0.77 and 0.94. There was an indication of a somewhat higher construct validity when participants filled out questionnaires using paper-and-pencil. We conclude that the LSAS-SR, SIAS, and SPS can be administered via the Internet with maintained psychometric properties.

Internet-delivered exposure and mindfulness based therapy for irritable bowel syndrome - A randomized controlled trial

The aim of this study was to investigate if cognitive behavior therapy (CBT) based on exposure and mindfulness exercises delivered via the Internet would be effective in treating participants with irritable bowel syndrome (IBS). Participants were recruited through self-referral. Eighty-six participants were included in the study and randomized to treatment or control condition (an online discussion forum). One participant was excluded after randomization. The main outcome measure was IBS-symptom severity and secondary measures included IBS-related quality of life, GI-specific anxiety, depression and general functioning. Participants were assessed at pre-treatment, post-treatment and 3 month follow-up (treatment condition only). Four participants (5% of total sample) in the treatment condition did not participate in post-treatment assessment. Participants in the treatment condition reported a 42% decrease and participants in the control group reported a 12% increase in primary IBS-symptoms. Compared to the control condition, participants in the treatment group improved on all secondary outcome measures with a large between group effect size on quality of life (Cohens d = 1.21). We conclude that CBT-based on exposure and mindfulness delivered via the Internet can be effective in treating IBS-patients, alleviating the total burden of symptoms and increasing quality of life.

Bilateral regulation of glutamate tissue and extracellular levels in caudate-putamen by midbrain dopamine neurons

Tissue levels and in vivo release of glutamate were measured in caudate-putamen of rat brain after a unilateral 6-hydroxydopamine lesion of meso-striatal/meso-cortico-limbic dopamine neurons. The results were compared with glutamate levels from corresponding regions in sham-injected animals. The unilateral dopamine lesion induced a bilateral increase of tissue levels of glutamate (45% ipsilateral and 39% contralateral to the lesion). Extracellular levels of glutamate as measured by microdialysis were also bilaterally increased (107% ipsilateral and 94% contralateral to the lesion). The results indicate that mesencephalic dopamine neurons regulate neuronal glutamate in ipsilateral as well as contralateral caudate-putamen.

Internet-Based Cognitive Behavior Therapy vs. Cognitive Behavioral Group Therapy for Social Anxiety Disorder: A Randomized Controlled Non-inferiority Trial

Background and Aims Cognitive behavioral group therapy (CBGT) is an effective, well-established, but not widely available treatment for social anxiety disorder (SAD). Internet-based cognitive behavior therapy (ICBT) has the potential to increase availability and facilitate dissemination of therapeutic services for SAD. However, ICBT for SAD has not been directly compared with in-person treatments such as CBGT and few studies investigating ICBT have been conducted in clinical settings. Our aim was to investigate if ICBT is at least as effective as CBGT for SAD when treatments are delivered in a psychiatric setting. Methods We conducted a randomized controlled non-inferiority trial with allocation to ICBT (n = 64) or CBGT (n = 62) with blinded assessment immediately following treatment and six months post-treatment. Participants were 126 individuals with SAD who received CBGT or ICBT for a duration of 15 weeks. The Liebowitz Social Anxiety Scale (LSAS) was the main outcome measure. The following non-inferiority margin was set: following treatment, the lower bound of the 95 % confidence interval (CI) of the mean difference between groups should be less than 10 LSAS-points. Results Both groups made large improvements. At follow-up, 41 (64%) participants in the ICBT group were classified as responders (95% CI, 52%–76%). In the CBGT group, 28 participants (45%) responded to the treatment (95% CI, 33%–58%). At post-treatment and follow-up respectively, the 95 % CI of the LSAS mean difference was 0.68–17.66 (Cohen’s d between group = 0.41) and −2.51–15.69 (Cohen’s d between group = 0.36) favoring ICBT, which was well within the non-inferiority margin. Mixed effects models analyses showed no significant interaction effect for LSAS, indicating similar improvement across treatments (F = 1.58; df = 2, 219; p = .21). Conclusions ICBT delivered in a psychiatric setting can be as effective as CBGT in the treatment of SAD and could be used to increase availability to CBT. Trial Registration ClinicalTrials.gov NCT00564967