Ten month outcome of cognitive behavioural therapy v. interpersonal psychotherapy in patients with major depression: a randomised trial of acute and maintenance psychotherapy.

BACKGROUND: Cognitive behaviour therapy (CBT) and interpersonal psychotherapy (IPT) are the most studied psychotherapies for treatment of depression, but they are rarely directly compared particularly over the longer term. This study compares the outcomes of patients treated with CBT and IPT over 10 months and tests whether there are differential or general predictors of outcome. METHODS: A single centre randomised controlled trial (RCT) of depressed outpatients treated with weekly CBT or IPT sessions for 16 weeks and then 24 weeks of maintenance CBT or IPT. The principle outcome was depression severity measured using the MADRS. Pre-specified predictors of response were in four domains: demographic depression, characteristics, comorbidity and personality. Data were analysed over 16 weeks and 40 weeks using general linear mixed effects regression models. RESULTS: CBT was significantly more effective than IPT in reducing depressive symptoms over the 10 month study largely because it appeared to work more quickly. There were no differential predictors of response to CBT v. IPT at 16 weeks or 40 weeks. Personality variables were most strongly associated with overall outcome at both 16 weeks and 40 weeks. The number of personality disorder symptoms and lower self-directness and reward dependence scores were associated with poorer outcome for both CBT and IPT at 40 weeks. CONCLUSIONS: CBT and IPT are effective treatments for major depression over the longer term. CBT may work more quickly. Personality variables are the most relevant predictors of outcome.

Characterization of the leukemogenic potential of distal cytoplasmic CSF3R truncation and missense mutations.

An increasing number of variants of unknown significance are being identified in leukemia patients with the application of deep sequencing and these include CSF3R cytoplasmic mutations. Previous studies have demonstrated oncogenic potential of certain CSF3R truncation mutations prior to internalization motifs. However, the oncogenic potential of truncating the more distal region of CSF3R cytoplasmic domain as well as cytoplasmic missense mutations remains uncharacterized. Here we identified that CSF3R distal cytoplasmic truncation mutations (Q793-Q823) also harbored leukemogenic potential. Mechanistically, these distal cytoplasmic truncation mutations demonstrated markedly decreased receptor degradation, probably owing to loss of the de-phosphorylation domain (residues N818-F836). Furthermore, all truncations prior to Q823 demonstrated increased expression of the higher molecular weight CSF3R band, which is shown to be essential for the receptor surface expression and the oncogenic potential. We further demonstrated that sufficient STAT5 activation is essential for oncogenic potential. In addition, CSF3R K704A demonstrated transforming capacity due to interruption of receptor ubiquitination and degradation. In summary, we have expanded the region of the CSF3R cytoplasmic domain in which truncation or missense mutations exhibit leukemogenic capacity, which will be useful for evaluating the relevance of CSF3R mutations in patients and helpful in defining targeted therapy strategies.

Was it something I did wrong? A qualitative analysis of parental perspectives of their child's bipolar disorder.

The aims of this study were to examine parental views on the onset of symptoms, impact on functioning and meanings attributed to their child's bipolar disorder. Early onset bipolar disorder impacts on development and functioning across multiple domains. Psychosocial disability fluctuates in parallel with changes in affective symptoms and may significantly affect family members. This study utilized descriptive statistical data and qualitative data from parental self-reports of 85 participants in a trial of psychotherapy for young people (15-34 years) with bipolar disorder. A content analysis was conducted on the written self-reports. Most parents identified the onset of depressive symptoms in their child by early adolescence, but it was not until late adolescence, or later, that parents noted symptoms of mania. The onset of symptoms during a crucial period of development had a considerable impact on social and occupational functioning. Without prompting, the parents took the opportunity to attempt to make sense of the diagnosis by attributing its onset to childhood adversity, parenting or substance misuse. Parents often blame themselves for the development of bipolar disorder in their child. Nursing care for clients with bipolar disorder could include interventions for the family to help them understand and manage the disorder. Such interventions could include: psycho-education, communication enhancement and problem-solving skills training.

Two sides of the same coin: caring for a person with bipolar disorder.

The aim of this paper was to gain an in-depth understanding of the way the lives of individuals supporting someone diagnosed with bipolar disorder. Bipolar disorder is a severe, recurrent and chronic mental disorder that has a significant impact on the lives of those who experience it and the people supporting them. It is often the subsyndromal symptoms that cause major impairment in functioning and can have financial, social, interpersonal and health impacts for carers. A qualitative thematic analysis was chosen to enable an in-depth exploration of participants' experiences. Twelve participants were interviewed using a semi-structured interview and the data were analysed to identify the themes that represented the participants' experiences. The predominant theme that emerged, two sides of the same coin, described the positive and negative aspects of being an informal carer for a person with bipolar disorder. This theme is constituted by two sub-themes: (1) 'I am a much more compassionate person'; and (2) 'It's tough and it's a sacrifice'. Mental health nurses could support informal caregivers more by providing care that demonstrates an understanding of the complexities associated with bipolar disorder and utilizes a collaborative approach to care that actively involves informal caregivers.

Measures of temperament and character are differentially impacted on by depression severity.

BACKGROUND: Cloninger's Temperament and Character Inventory (TCI) is a widely used measure of personality. Two scales of the TCI, harm avoidance (HA) and self directedness (SD), have been shown to be influenced by depressed mood. We examined how the seven TCI scales and their subscales are correlated with depression severity before and after treatment. We also examined whether changes in personality measures could be attributed to changes in depression severity. METHODS: Two clinical samples of depressed out-patients were recruited for trials to examine predictors of treatment response to antidepressants (N=195) and psychotherapies (N=177). Assessment included the Montgomery-Asberg depression rating scales (MADRS), Hopkins Symptom Checklist (SCL-90) and TCI at baseline and after treatment. RESULTS: After treatment, in both samples, depression severity correlated significantly with HA and negatively with SD. Multiple regression analysis revealed that changes in SD and HA over treatment were related to improvement in depression. In the psychotherapy trial baseline MADRS scores correlated with low SD and high HA. LIMITATIONS: The trial results are applicable to mild-moderately depressed out-patients. CONCLUSIONS: Depression severity influences the total scales and most of the subscale measures of HA and SD. Some personality traits, as measured by the TCI, were not impacted upon by mood. Clinically mood should be taken into account when assessing personality measures of negative affect using the TCI.

Orosomucoid influences the response to antidepressants in major depressive disorder.

Orosomucoid, an acute phase protein, carries basic drugs including antidepressants in plasma. Elevated levels have been reported in patients with depression. It has yet to be established whether orosomucoid concentration influences antidepressant response. The orosomucoid gene (ORM1) is polymorphic and the protein isoforms have differing pharmacokinetic properties which could alter plasma profile and blood brain barrier transport of antidepressants. Outpatients (n = 157) in a randomised control trial of fluoxetine versus nortriptyline were genotyped for the ORM1 variants. Plasma concentrations of acute phase proteins were also measured. Outcomes were the completion of an adequate six week trial of antidepressant and response. Response was defined as an improvement >/=60% on the Montgomery-Asperg Depression Rating Scale (MADRS) over six weeks. The first notable finding was that individuals with an ORM1*S/*S genotype were less likely to complete an adequate six week trial of an antidepressant (OR = 4.707, 95% CI 1.769-12.527, P = 0.002). The second was that higher orosomucoid concentrations were found in antidepressant non-responders (91.4%) than responders (79.1%) (F1, 106 = 5.669, P = 0.019). These findings highlight the potential importance of variables such as orosomucoid which impact on drug availability on the therapeutic efficacy of antidepressant drugs.

Antidepressant treatment is associated with a reduction in suicidal ideation and suicide attempts.

OBJECTIVE: To measure changes in suicidal behaviours during 6 months of treatment with antidepressants. METHOD: A group of depressed patients (n = 195) were assessed for suicidal behaviours in the 6 months prior to treatment. They were prospectively assessed for suicidal behaviours during 6 months of treatment with antidepressants. RESULTS: Patients who made suicide attempts fell from 39 in the 6 months prior to treatment to 20 during treatment. Significant suicidal ideation reduced from 47% at baseline to 14% at 3 weeks remaining below this during the rest of the treatment. Twenty patients had emergent suicidal ideation; five of them had not experienced some level of suicidal behaviour in the 6 months prior to treatment. CONCLUSION: Suicide behaviours are common in depressed out-patients. Antidepressant treatment is associated with a rapid and significant reduction in suicidal behaviours. The rate of emergent suicidal behaviour was low and the risk benefit ratio for antidepressants appears to favour their use.

A differential response to nortriptyline and fluoxetine in melancholic depression: the importance of age and gender.

OBJECTIVE: To consider the impact of age and gender on the antidepressant response to nortriptyline and fluoxetine in melancholic depression. METHOD: Of 191 depressed patients, 113 met study criteria for melancholia. All patients were randomized to receive either fluoxetine or nortriptyline. Response rates, defined as an improvement of 60% or more on the Montgomery Asberg Depression Rating Scale over 6 weeks of antidepressant treatment on an intention to treat basis, were examined by age, and by age and gender. RESULTS: Melancholic depressed patients 40 years or older, especially men, had a markedly superior response to nortriptyline compared with fluoxetine. Conversely, melancholic depressed patients, age 18-24 years, especially women, had a markedly superior response to fluoxetine. CONCLUSION: Age and gender appear to be critical variables in understanding differential antidepressant responses to tricyclic antidepressants and selective serotonin reuptake inhibitors in melancholic depression.

Histological and ultrastructural studies of rats exposed to carbaryl.

The aim of the study was to assess the general toxic effects of dermally applied carbaryl, based on histological and ultrastructural examinations of internal organs and to relate these effects to earlier own studies where 14C carbaryl was used for determining the pesticide penetration. The pesticide was applied in doses of 1/5 and 1/10 LD50, administered to the tail skin of male Wistar rats 4 hours daily, for 4 weeks except Saturdays and Sundays. After the experiment, the animals were anaesthetized and the following organs were taken for histological study: brain, lung, heart, liver, kidney, skin from the site of exposure and skin from a place at least 2 cm distant from the exposure site. Lung, liver, kidney, heart and skin were used for ultrastructural studies. Dermal application of carbaryl resulted only in slight histological changes in skin, liver, brain and lung. Even in brain and liver, where large amounts of 14C carbaryl, compared to other organs (lung, kidney, heart), where the intensity of histologic changes was earlier stated to below. Ultrastructural changes were observed in skin, liver, lung, heart and kidney.

Neurotoxic effect of dermally-applied chlorpyrifos and cypermethrin in Wistar rats.

The aim of the study was to evaluate the neurotoxic effect of a dermally-applied mixture of chlorpyrifos and cypermethrin in rats based on cognitive function, activity of the blood cholinesterase and brain acetylcholinesterase, as well as histologic brain examination. Nurelle D 550 EC (500 g of chlorpyrifos and 50 g of cypermethrin) was used in the study. The application liquid was in the form of a water solution. The investigation covered eight groups of animals: six experimental groups and two control groups, of 15 rats each. Experimental groups received 5.6 mg/cm2 chlorpyrifos and 0.5 mg/cm2 cypermethrin, or 27.8 mg/cm2 chlorpyrifos and 2.7 mg/cm2 cypermethrin dermally, for one day, one week and four weeks, except for Saturdays and Sundays. The preparations examined were applied to the tail skin of rats. The animals were anaesthetized at the end of exposure period. Plasma cholinesterase and brain acetylcholinesterase activities were determined. The brain for histological examination was perfused with a solution of methanol, formalin and glacial acetic acid, and the sections stained by the Nissel method. The behaviour of the animals was evaluated in the open field test four times: before exposure, and after one, two and four weeks of the experiment. The results of the study showed that chlorpyrifos and cypermethrin applied in a mixture caused an inhibition of cholinesterase and acetylcholinesterase activity and elicited the pycnosis of brain neurocytes.

Oral toxicity of deltamethrin and fenvalerate in Swiss mice.

The study was conducted on female and male Swiss mice with body mass of 20-30 g. The experimental animals were administered deltamethrin in concentrations of 5 mg/kg b.m. (1/10 LD50) and 25 mg/kg b.m. (1/2 LD50), or fenvalerate in the doses of 10 mg/kg b.m. (1/10 LD50) and 50 mg/kg b.m. (1/2 LD50). Pyrethroids were administered intragastrically once a day for 28 days. Parallel studies were conducted in two control groups. The following organs were taken for histologic examinations: liver, kidney, lung, heart and spleen. Blood was taken from the heart for hematologic tests. The total number of erythrocytes and leukocytes, the percentage of neutrophils and lymphocytes, as well as the level of hemoglobin and hematocrit were determined. Deltamethrin and fenvalerate caused degenerative changes in the liver and kidneys in Swiss mice. Changes were more intense in male mice which were administered deltamethrin, and in female mice which received fenvalerate. Irrespective of the dose, the pyrethroids examined stimulated erythropoiesis and synthesis of hemoglobin in male Swiss mice, while in female mice the administration of deltamethrin in the dose of 1/10 LD50 resulted in the suppression of erythropoiesis and hemoglobin synthesis. Both in male and female mice, deltamethrin and fenvalerate--irrespective of the dose--caused a general increase in the number of leukocytes.

Dermal absorption and distribution of (14)C carbaryl in Wistar rats.

The level of (14)C carbaryl was determined in blood (leukocytes, erythrocytes, all blood cells, plasma) and organs (brain, heart, lungs, liver, spleen, skin at the site of exposure) of male Wistar rats after dermal administration. The application liquid was (14)C carbaryl solution in 96% ethyl alcohol. This preparation, possessing an activity of 670 kBq/ml, containing 1.67 mg of carbaryl, was applied to the skin of the tail according to Massmann's method in own modification. The amount of the preparation per 1 cm(2) of the tail skin was 0.19 mg of carbaryl (74.4 kBq). The tails of experimental rats were exposed to (14)C carbaryl by soaking for 4 h daily: once, twice or three times. Beta radiation from (14)C was measured in homogenized organs (brain, heart, lungs, liver, skin) and in blood by computer controlled Wallac scintillation counter Model 1409, using Multi Calc software. The dermal absorption of carbaryl at the site of exposure and in the surrounding area of about 2 cm was observed already during 4 hour exposure. Carbaryl reached plasma within 4 h of a single dermal exposure and penetrated into leukocytes, erythrocytes, heart, liver, lung, kidney and brain. The largest amount of (14)C carbaryl, about 2% of absorbed dose, was detected in liver

The contribution of temperament, childhood neglect, and abuse to the development of personality dysfunction: a comparison of three models.

We examined the contribution of temperament, childhood neglect, and abuse to the development of personality dysfunction as postulated in three different but correlated models of personality: the psychobiological, Vaillant's psychoanalytic, and DSM psychopathology models. Character, defense style, and personality disorder symptomatology (the dependent variables), and temperament, childhood neglect, and abuse (the independent variables) were assessed in 168 depressed outpatients. High harm avoidance (temperament) tended to be the strongest and most consistent risk factor across the three models. Deficient parental care predicted personality dysfunction, however low care was not consistently predictive across all three models. Emotional/psychological abuse and actual physical abuse were risk factors for increasing personality disorder symptomatology only. Childhood sexual abuse was not as predictive of personality dysfunction as might be expected, thereby raising questions as to the importance placed on child sexual abuse as a general risk factor for personality psychopathology.

Comparison between noradrenergic and serotonergic medications using the social adjustment scale: is drive enhancement necessary for recovery of social functioning?

The Social Adjustment Scale (SAS) was used to assess social functioning sequentially over 13 weeks in a group of 188 depressed outpatients randomized to either the noradrenergic antidepressant, nortriptyline, or the selective serotonin reuptake inhibitor, fluoxetine. Over the period of 13 weeks, there were no differences in total SAS scores between the nortriptyline and the fluoxetine group. In comparing the SAS subscale scores, which may measure different areas of motivation and behaviour (drive), there were differences between the two groups in only two subscales. At 13 weeks, the group randomized to fluoxetine were more impaired in marital role (p = 0.026) whereas, at 6 weeks, the group randomized to nortriptyline were more impaired in friction scores (p = 0.012). These results do not support the concept of specific augmentation of drive-related behaviour by noradrenergic medication. This challenges the earlier findings relating to drive enhancement and social adjustment using such medication.