Long-term efficacy of Internet-based cognitive behavior therapy for obsessive-compulsive disorder with or without booster: a randomized controlled trial.

BACKGROUND: As relapse after completed cognitive behavior therapy (CBT) for obsessive-compulsive disorder (OCD) is common, many treatment protocols include booster programs to improve the long-term effects. However, the effects of booster programs are not well studied. In this study, we investigated the long-term efficacy of Internet-based CBT (ICBT) with therapist support for OCD with or without an Internet-based booster program. METHOD: A total of 101 participants were included in the long-term follow-up analysis of ICBT. Of these, 93 were randomized to a booster program or no booster program. Outcome assessments were collected at 4, 7, 12 and 24 months after receiving ICBT. RESULTS: The entire sample had sustained long-term effects from pre-treatment to all follow-up assessments, with large within-group effect sizes (Cohen's d = 1.58-2.09). The booster group had a significant mean reduction in OCD symptoms compared to the control condition from booster baseline (4 months) to 7 months, but not at 12 or 24 months. Participants in the booster group improved significantly in terms of general functioning at 7, 12 and 24 months, and had fewer relapses. Kaplan-Meier analysis also indicated a significantly slower relapse rate in the booster group. CONCLUSIONS: The results suggest that ICBT has sustained long-term effects and that adding an Internet-based booster program can further improve long-term outcome and prevent relapse for some OCD patients.

Effectiveness of internet-based cognitive behaviour therapy for panic disorder in routine psychiatric care.

OBJECTIVE: Guided Internet-based cognitive behaviour therapy (ICBT) for panic disorder has been shown to be efficacious in several randomized controlled trials. However, the effectiveness of the treatment when delivered within routine psychiatric care has not been studied. The aim of this study was to investigate the effectiveness of ICBT for panic disorder within the context of routine psychiatric care. METHOD: We conducted a cohort study investigating all patients (n = 570) who had received guided ICBT for panic disorder between 2007 and 2012 in a routine care setting at an out-patient psychiatric clinic providing Internet-based treatment. The primary outcome measure was the Panic Disorder Severity Scale-Self-report (PDSS-SR). RESULTS: Participants made large improvements from screening and pretreatment assessments to posttreatment (Cohen's d range on the PDSS-SR = 1.07-1.55). Improvements were sustained at 6-month follow-up. CONCLUSION: This study suggests that ICBT for panic disorder is as effective when delivered in a routine care context as in the previously published randomized controlled trials.

Cost-effectiveness and long-term effectiveness of internet-based cognitive behaviour therapy for severe health anxiety.

BACKGROUND: Severe health anxiety is a common condition associated with functional disability, making it a costly disorder from a societal perspective. Internet-based cognitive behaviour therapy (ICBT) is a promising treatment but no previous study has assessed the cost-effectiveness or long-term outcome of ICBT for severe health anxiety. The aim of this study was to investigate the cost-effectiveness and 1-year treatment effects of ICBT for severe health anxiety. METHOD: Cost-effectiveness and 1-year follow-up data were obtained from a randomized controlled trial (RCT) comparing ICBT (n = 40) to an attention control condition (CC, n = 41). The primary outcome measure was the Health Anxiety Inventory (HAI). A societal perspective was taken and incremental cost-effectiveness ratios (ICERs) were calculated using bootstrap sampling. RESULTS: The main ICER was -£1244, indicating the societal economic gain for each additional case of remission when administering ICBT. Baseline to 1-year follow-up effect sizes on the primary outcome measure were large (d = 1.71-1.95). CONCLUSIONS: ICBT is a cost-effective treatment for severe health anxiety that can produce substantial and enduring effects.

Changes in dopamine D2-receptor binding are associated to symptom reduction after psychotherapy in social anxiety disorder.

The dopamine system has been suggested to play a role in social anxiety disorder (SAD), partly based on molecular imaging studies showing reduced levels of striatal dopaminergic markers in patients compared with control subjects. However, the dopamine system has not been examined in frontal and limbic brain regions proposed to be central in the pathophysiology of SAD. In the present study, we hypothesized that extrastriatal dopamine D2-receptor (D2-R) levels measured using positron emission tomography (PET) would predict symptom reduction after cognitive behavior therapy (CBT). Nine SAD patients were examined using high-resolution PET and the high-affinity D2-R antagonist radioligand [(11)C]FLB 457, before and after 15 weeks of CBT. Symptom levels were assessed using the anxiety subscale of Liebowitz Social Anxiety Scale (LSAS(anx)). At posttreatment, there was a statistically significant reduction of social anxiety symptoms (P<0.005). Using a repeated measures analysis of covariance, significant effects for time and time × LSAS(anx) change on D2-R-binding potential (BP(ND)) were shown (P<0.05). In a subsequent region-by-region analysis, negative correlations between change in D2-R BP(ND) and LSAS(anx) change were found for medial prefrontal cortex and hippocampus (P<0.05). This is the first study to report a direct relationship between symptom change after psychological treatment and a marker of brain neurotransmission. Using an intra-individual comparison design, the study supports a role for the dopamine system in cortical and limbic brain regions in the pathophysiology of SAD.

Internet-based cognitive behaviour therapy for obsessive-compulsive disorder: a randomized controlled trial.

BACKGROUND: Cognitive behaviour therapy (CBT) is an effective treatment for obsessive-compulsive disorder (OCD) but access to CBT is limited. Internet-based CBT (ICBT) with therapist support is potentially a more accessible treatment. There are no randomized controlled trials testing ICBT for OCD. The aim of this study was to investigate the efficacy of ICBT for OCD in a randomized controlled trial. METHOD: Participants (n=101) diagnosed with OCD were randomized to either 10 weeks of ICBT or to an attention control condition, consisting of online supportive therapy. The primary outcome measure was the Yale-Brown Obsessive Compulsive Scale (YBOCS) administered by blinded assessors. RESULTS: Both treatments lead to significant improvements in OCD symptoms, but ICBT resulted in larger improvements than the control condition on the YBOCS, with a significant between-group effect size (Cohen's d) of 1.12 (95% CI 0.69-1.53) at post-treatment. The proportion of participants showing clinically significant improvement was 60% (95% CI 46-72) in the ICBT group compared to 6% (95% CI 1-17) in the control condition. The results were sustained at follow-up. CONCLUSIONS: ICBT is an efficacious treatment for OCD that could substantially increase access to CBT for OCD patients. Replication studies are warranted.

Clinical and genetic outcome determinants of Internet- and group-based cognitive behavior therapy for social anxiety disorder.

OBJECTIVE: No study has investigated clinical or genetic predictors and moderators of Internet-based cognitive behavior therapy (ICBT) compared with cognitive behavioral group therapy for (CBGT) for SAD. Identification of predictors and moderators is essential to the clinician in deciding which treatment to recommend for whom. We aimed to identify clinical and genetic (5-HTTLPR, COMTval158met, and BDNFval66met) predictors and moderators of ICBT and CBGT. METHOD: We performed three types of analyses on data from a sample comprising participants (N = 126) who had undergone ICBT or CBGT in a randomized controlled trial. Outcomes were i) end state symptom severity, ii) SAD diagnosis, and iii) clinically significant improvement. RESULTS: The most stable predictors of better treatment response were working full time, having children, less depressive symptoms, higher expectancy of treatment effectiveness, and adhering to treatment. None of the tested gene polymorphisms were associated with treatment outcome. Comorbid general anxiety and depression were moderators meaning that lower levels were associated with a better treatment response in ICBT but not in CBGT. CONCLUSION: We conclude that demographic factors, symptom burden, adherence, and expectations may play an important role as predictors of treatment outcome. The investigated gene polymorphisms do not appear to make a difference.

Delayed stress-induced increase in tissue level of cholecystokinin in rat prefrontal cortex: modulation by microdialysis probe implantation and systemic ketamine.

In the brain, the neuropeptide cholecystokinin (CCK) appears to be involved in the mediation of stress responses. Here we provide new evidence that mild stress induces long-term changes in CCK-like immunoreactivity (CCK-LI) in the prefrontal cortex (PFC). The changes in CCK-LI show a biphasic pattern, with a decrease 20 min after and an increase 8 h after mild stress. These changes seem to be region specific. Measurement of CCK mRNA in prefrontal cortex neurons 4 or 8 h after the stress stimulus did not reveal changes in mRNA levels, suggesting that afferent CCK-containing neuron terminals may be more affected than local cortical CCK-ergic neurons. Furthermore, treatment with the glutamate NMDA receptor antagonist ketamine, led to more pronounced decreases in CCK-LI observed within 20 min after mild stress and counteracted the stress induced increase in cortical CCK-LI levels observed at 8 h. Implantation of a microdialysis probe in the PFC affected the response to mild stress, with no significant decrease in the CCK-LI level 20 min after, and attenuated reactivity to stress 8 h after the saline injection. Our results indicate that a mild stressful stimulus such as an intraperitoneal saline injection may have long-lasting effects on CCK-ergic transmission in the PFC. The use of microdialysis to study stress induced in vivo CCK-LI release in awake animals may, however, be significantly compromised by the impact of the microdialysis probe implantation on CCK-ergic mechanisms in the PFC. In addition, we hypothesize that subanesthetic doses of the psychotomimetic drug ketamine interfere with CCK-ergic mechanisms in the PFC during stress.

Effects of antipsychotic drugs on cholecystokinin and preprotachykinin (substance P) mRNA expression in the rat hippocampal formation.

To assess the involvement of substance P (SP) and cholecystokinin (CCK) in the effects of antipsychotic drugs, preprotachykinin-A (PPT-A) and CCK mRNA expression was studied in the hippocampal formation using in situ hybridisation following 21 daily i.p. injections with the typical antipsychotic drug haloperidol (1 mg/kg) and the atypical drug clozapine (15 mg/kg). PPT-A mRNA levels were increased in the hippocampal CA3 subregion and in the entorhinal cortex after haloperidol, whereas a decrease was observed in the CA1 after clozapine. CCK mRNA levels increased in the CA1, the entorhinal cortex and in hilus, following both haloperidol and clozapine. It is suggested that earlier findings of increased SP levels in the hippocampal formation of schizophrenics may be a consequence of haloperidol treatment and that reduced hippocampal CCK and CCK mRNA levels found earlier in schizophrenics do not result from antipsychotic drug treatment. These results are consonant to the hypothesis that increased cortical CCK transmission may be beneficial in the treatment of psychosis.

Cholecystokinin CCK(B) receptor mRNA isoforms: expression in schizophrenic brains.

In the light of earlier findings of reduced cholecystokinin (CCK) peptide and CCK mRNA levels in the cerebral cortex, we have used in situ hybridization to examine possible regulation of mRNAs coding for two isoforms of the CCK(B) receptor in frontal cortex (Brodmann's area 10) of schizophrenic patients. The hybridizations revealed a 51% decrease of the full length CCK(B) receptor mRNA in the outer layers (II-III) of the frontal cortex. The corresponding alterations for the truncated isoform were a 65% reduction in the outer layers and a 62% reduction in the inner layers (IV-VI) of the frontal cortex. This strengthens the hypothesis that CCKergic transmission in this part of the brain is involved in the pathophysiology of schizophrenia.

[Increasing abuse of psychostimulants is alarming. New findings confirm the mechanisms behind cocaine and amphetamine addiction]. / Okande missbruk av psykostimulantia oroar. Nya rön klarlägger mekanismerna bakom kokain- och amfetaminberoende.

Amphetamine and cocaine are highly addictive psychostimulant drugs with potent actions on affect and motor activity. Psychostimulants exert their effects by interaction with monoamine transport carriers on cell membranes. Dopamine pathways extending from the brain stem to the basal ganglia, limbic structures, and cerebral cortex are generally considered to constitute the neuroanatomical substrates underlying motivation, reward, and motor function. Repeated use of psychostimulants is characterised by both tolerance (e.g., euphoria) and sensitisation (e.g., motor activation), and abstinence by craving and anhedonia. Neuronal systems, molecular alterations, and treatment regimens associated with psychostimulants are currently the subjects of discussion.

A tachykinin NK1 receptor antagonist, CP-122,721-1, attenuates kainic acid-induced seizure activity.

Substance P (SP) can play an important role in neuronal survival. To analyze the role of SP in excitotoxicity, kainic acid (KA) was administered to rats and in situ hybridization was used to analyze the levels of the SP encoding preprotachykinin-A (PPT-A) mRNA in striatal and hippocampal subregions 1, 4, and 24 h and 7 days after KA. In striatum and piriform cortex, PPT-A mRNA peaked 4 h after KA while in hippocampus, levels peaked after 24 h. KA caused seizures and neuronal toxicity as indicated by a reduction of the number of neurons in the hippocampal CA1 subregion after 7 days. KA was later administered alone or following pretreatment with the tachykinin NK1 receptor antagonist CP-122,721-1 (0.3 mg/kg). The pretreatment decreased seizure activity and a negative correlation was found between seizure activity and survival of CA1 neurons. Conclusively, treatment with CP-122,721-1 has a seizure inhibiting property and may possibly counteract KA-induced nerve cell death in CA1.

GABA release and GAD67 mRNA expression in rat hippocampus following entorhinal cortex activation.

This study investigate the effect of stimulation of glutamatergic afferents originating in the entorhinal cortex on possible changes of GABAergic transmission in the CA1 subregion of the hippocampus. Microdialysis was used to monitor extracellular GABA and in situ hybridization to measure levels of glutamic acid decarboxylase67 (GAD67) mRNA. A dose-dependent increase in extracellular levels of GABA in the dorsal CA1 subregion was detected following injection of 2.4 and 9.6 micrograms quisqualate into the lateral entorhinal cortex whereas 0.24 microgram had no effect. The GABA increase was attenuated by local administration of tetrodotoxin (TTX), indicating neuronal origin. A 60% decrease and a 160% increase were seen in levels of GAD67 mRNA in the CA1 following injection of 0.24 and 9.6 micrograms quisqualate, respectively. This study provides evidence of an entorhinal cortex influenced stimulatory effect on GABAergic activity in the CA1. However, no direct relationship was found between stimulated GABA release and subsequently measured GAD67 mRNA levels. The increased GABA release and the apparent adaptive increase in GAD67 mRNA levels by the strongest stimulation may be due to an endogenous inhibitory neuroprotective response to an excitotoxic influence.

Differential effects of single and repeated ketamine administration on dopamine, serotonin and GABA transmission in rat medial prefrontal cortex.

Cognitive functions regulated by the prefrontal cortex are sensitive to changes in dopaminergic and serotoninergic transmission. The non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist ketamine influences dopaminergic transmission and induces psychotic symptoms in normal and schizophrenic individuals. This study examined the effect of single and repeated ketamine (25 mg/kg, i.p.) administration on extracellular levels of dopamine, GABA and the serotonin metabolite 5-hydroxyindoleacetic (5-HIAA) acid in the medial prefrontal cortex using in vivo microdialysis in conscious rat. In line with earlier studies, we observed a transient five-fold increase in dopamine release following single ketamine administration in drug naive animals. However, we also observed a two-fold increase in basal dopamine levels and an almost complete attenuation of the ketamine-induced increase in dopamine release in animals pre-treated with ketamine once daily for 7 days. Extracellular 5-HIAA levels were increased by ketamine in both drug naive and even more enhanced in ketamine-pre-treated animals but without a change in basal 5-HIAA levels. GABA levels were unaffected by either single or repeated ketamine administration. We demonstrate evidence for a differential effect of single and repeated ketamine administration on dopamine, serotonin and GABA transmission in the medial prefrontal cortex. We provide new evidence for a complex adaptation of neurotransmission following repeated NMDA receptor blockade whereby in the presence of increased basal dopamine levels the ketamine-induced increase in dopamine is attenuated and the increase in 5-HIAA is enhanced. It appears from our results that ketamine pre-treatment reduces the dynamics of dopaminergic transmission in the prefrontal cortex and may possibly alter the balance between dopamine and serotonin transmission.

Effect of chronic antipsychotic drug treatment on preprosomatostatin and preprotachykinin A mRNA levels in the medial prefrontal cortex, the nucleus accumbens and the caudate putamen of the rat.

In situ hybridization histochemistry was used to study the expression of preprosomatostatin (PPSOM) and preprotachykinin A (PPT-A) mRNA in the medial prefrontal cortex (mPFC), the nucleus accumbens (NAC) and the caudate putamen (CP) of the rat after chronic (21 days) treatment with the classical antipsychotic drug haloperidol (1 mg/kg i.p.), the atypical antipsychotic drugs clozapine (15 mg/kg i.p.) and amperozide (5 mg/kg i.p.), and the selective dopamine (DA)-D2/D3 receptor antagonist raclopride (2 mg/kg i.p.). Whereas amperozide markedly elevated the numerical density of PPSOM mRNA expressing neurons in the mPFC (52%), the other drugs did not significantly affect PPSOM mRNA levels in any of the brain regions studied. Amperozide also altered PPT-A mRNA expression in the mPFC, i.e. a decrease (22%) was found. Of the other drugs tested only haloperidol significantly decreased PPT-A mRNA levels in the NAC shell (14%), in the dorso-lateral CP (19%) and in the medial CP (15%). In view of the differences between amperozide and the other drugs studied, as regards both pre-clinical and clinical characteristics, we suggest that the specific effects of amperozide on PPSOM and PPT-A mRNA in the mPFC may be related to its 5-HT releasing action in the frontal cortex, an effect possibly caused by its alpha2-adrenoceptor blocking activity. This effect, in turn, may be related to an antidepressant-like action that this compound exhibits in animal studies. The decrease in PPT-A mRNA levels seen after the haloperidol treatment is probably due to its potent DA-D2 receptor antagonism and may be related to side-effects, rather than therapeutic effects of this drug.

Decreased levels of preprotachykinin-A and tachykinin NK1 receptor mRNA in specific region of the rat striatum after electroconvulsive stimuli.

The effects of electroconvulsive stimuli on the expression of mRNAs coding for preprotachykinin-A and the substance P-sensitive tachykinin NK1 receptor were examined in subregions of the rat striatum. In the electroconvulsive stimuli-treated animals, a 43% decrease in preprotachykinin-A mRNA was detected in the dorso-lateral caudate-putamen as compared to sham electroconvulsive stimuli treated animals. A 75% decrease in numerical density of tachykinin NK1 receptor mRNA positive neurons was found in the caudal part of the nucleus accumbens core. These findings provide new evidence for selective effects of electroconvulsive stimuli on specific populations of neurons in the rat striatum.

Effects of chronic lithium and electroconvulsive stimuli on cholecystokinin mRNA expression in the rat brain.

This study compares the effect of lithium (Li+) and electroconvulsive stimuli (ECS), two treatments commonly used in the treatment of affective disorders, on CCK mRNA expression in the rat brain. Two groups of rats receiving either 4 week Li+ or vehicle food supplementation and two groups receiving 6 ECS or 6 sham ECS during 2 weeks were studied. A significant decrease in CCK mRNA levels was seen in the caudate putamen both after Li+ as compared to vehicle and ECS as compared to sham ECS, 27 and 25%, respectively. A small (10%), yet significant, decrease was also seen in the inner entorhinal cortex after Li+. The results indicate that both Li+ and ECS inhibit CCK synthesis in the caudate putamen and are consistent with other findings of presumed decreased dopaminergic action in this part of the brain following these treatments.

Glutamate release correlates with brain-derived neurotrophic factor and trkB mRNA expression in the CA1 region of rat hippocampus.

Synthesis of the neurotrophic factor brain-derived neurotrophic factor (BDNF) and its receptor TrkB in the hippocampus have been proposed to be influenced by endogenous glutamate. To test this hypothesis we have investigated if increases in BDNF and trkB mRNAs are associated with changes in the synaptic release of glutamate in the dorsal hippocampus in the conscious rat by combining the technique of in vivo microdialysis with in situ hybridization histochemistry. A 35% and 66% increase in extracellular levels of glutamate in the dorsal CA1 region was detected following injection into the lateral entorhinal cortex of 2.4 and 9.6 microg of the non-NMDA glutamate receptor agonist quisqualate, respectively. The increase in glutamate was attenuated by local administration of tetrodotoxin (TTX) indicating neuronal origin. Levels of BDNF and trkB mRNAs were increased in the hippocampus in a dose-dependent fashion following the stimulations. The extracellular levels of glutamate in individual animals correlated to the levels of BDNF and trkB mRNAs in the dorsal CA1 region of the hippocampus. This study provides for the first time evidence of an entorhinal cortex influenced concentration-dependent relationship between the release of endogenous glutamate in vivo and neuronal expression of mRNAs for BDNF and its receptor trkB in the hippocampus.

[Cholecystokinin receptors. A target for tomorrow's psychopharmaceuticals?]. / Kolecystokininreceptorer. Mål för morgondagens psykofarmaka?

The neuropeptide cholecystokinin (CCK) and its receptors are highly expressed in brain regions important for cognitive functions, emotions and the initiation of movements. Two high-affinity receptors exist for CCK, the A-and B-type. A number of ligands are developed for these receptors. Evidence for the involvement of CCK and its receptors in the pathofysiology of neuropsychiatric disorders is discussed. In addition, we discuss the possible use of CCK receptors ligands in the treatment of such disorders.

Neuronal coexistence of trkB and glutamic acid decarboxylase67 mRNAs in rat hippocampus.

We have in earlier studies shown that brain derived neurotrophic factor (BDNF) mRNA expression is increased in the hippocampus following stimulation of excitatory cortical afferents and spatial learning. Furthermore, we have observed that excitatory influence in the hippocampus seems to increase in vivo release of gamma-aminobutyric acid (GABA), indicated by microdialysis perfusion of the CA1 region. In this study we have investigated whether the receptor for BDNF, TrkB, may be expressed in GABA containing neurons in the CA1, thereby suggesting a possible role for BDNF in the trophic regulation of these neurons. We provide evidence of a neuronal coexistence of the mRNA encoding TrkB and glutamic acid decarboxylase, the key enzyme in the synthesis of GABA. This finding indicates that TrkB can be synthesized in GABA producing neurons in the hippocampus.