Gool, A.R. van

Randomised clinical trial: Escitalopram for the prevention of psychiatric adverse events during treatment with peginterferon-alfa-2a and ribavirin for chronic hepatitis C (Article)

2011-12-01T00:00:00Z

Background Treatment of hepatitis C with peginterferon and ribavirin is associated with psychiatric side-effects, frequently necessitating dose reduction or therapy cessation. Aim To assess the efficacy of prophylactic escitalopram to prevent psychiatric side-effects during peginterferon and ribavirin treatment in a randomised, double-blind, placebo-controlled trial. Methods Seventy-nine hepatitis C patients were treated with peginterferon and ribavirin. Patients received escitalopram (n = 40, 10 mg) or placebo (n = 39), which was initiated together with peginterferon and ribavirin. Primary outcomes were an increase of two points or more on the items reported sadness, inner tension and impaired concentration of the Montgomery-Asberg Depression Rating Scale, and hostile feelings of the Brief Anxiety Scale. Secondary outcome was the development of depression diagnosed by the Mini-International Neuropsychiatric Interview. Measurements were performed at baseline, week 4, 12 and 24 during anti-viral treatment, and 24 weeks thereafter. Results The incidence of psychiatric side-effects was significantly lower in patients treated with escitalopram compared with placebo for all primary and secondary outcomes, except for impaired concentration: reported sadness 27.5 vs. 48.7% (P = 0.052), inner tension 17.5 vs. 38.5% (P = 0.038), impaired concentration 55.0 vs. 66.7% (P = 0.288) and hostile feelings 22.5 vs. 43.6% (P = 0.046) (escitalopram vs. placebo, Chi-squared test). The sum scores of all four endpoints showed an overall beneficial effect of escitalopram (P = 0.009, Mann-Whitney U-test). Depression occurred in 12.5% of the patients in the escitalopram-group vs. 35.9% in the placebo-group (P = 0.015, Chi-squared test). Conclusions Prophylactic treatment with escitalopram is effective in the prevention of psychiatric side-effects during interferon-based treatment of hepatitis C.

Severe akathisia as a side effect of metoclopramide (Article)

2010-12-01T00:00:00Z

Case description A case of severe metoclopramide-induced akathisia in a breast cancer patient being treated with chemotherapy is presented, eventually culminating in hospital admission. In retrospect, this adverse effect was not recognized for several weeks because the prescription had not been properly recorded in the chart, the patient initially denied using the drug, and extensive psychological adjustment difficulties were also present. Conclusion Movement disorders as an adverse effect of metoclopramide have been described on a regular basis over the past decades. Case reports such as this confirm there is under-recognition of adverse effects and emphasize the need to take a comprehensive medication history and recognize well known side effects of medications such as metoclopramide.

The prefrontal cortex as a target for antipsychotic agents [De prefrontale cortex als aangrijpingspunt voor antipsychotica] (Article)

2010-01-01T00:00:00Z

Nitric oxide production and monoamine oxidase activity in cancer patients during interferon-a therapy (Article)

2009-10-01T00:00:00Z

Abstract Both increased and decreased nitric oxide (NO) synthesis have been reported in patients treated with interferon-alpha (IFN-alpha). Animal studies showed that IFN-alpha administration results in increased levels of biogenic amines, subsequent activation of monoamine oxidases (MAOs), and finally in a change in NO production due to the H(2)O(2) generated by MAOs. We examined the potential relationship between NO production in plasma and MAO-B activity in platelets of 43 cancer patients during 8 weeks of treatment with IFN-alpha. NO synthesis was quantitated by measuring both the ratio of citrulline and arginine (CIT/ARG-ratio) and total nitrite/nitrate (NOx) levels. Compared to baseline, MAO activity and NOx increased, while the CIT/ARG-ratio decreased. No associations were found between NOx, MAO and CIT/ARG-ratio. Only few associations were observed between changes in the biochemical parameters and changes in psychopathology induced by IFN-alpha, of which the association between changes in CIT and lassitude was the most consistent. The results suggest that peripheral NO production and MAO activity are unrelated to each other, and that peripheral changes in these biochemical parameters induced by IFN-alpha are unlikely to contribute to definite psychiatric disturbance.

Standard psychological consultations and follow up for women at increased risk of hereditary breast cancer considering prophylactic mastectomy (Article)

2009-03-31T00:00:00Z

Background: Women at increased (genetic) risk of breast cancer have to weigh the personal pros and cons of prophylactic mastectomy (PM) as an option to reduce their cancer risk. So far, no routine referral to a psychologist has been investigated for women considering PM. Aim of this study was to asses: 1) the acceptance of the offer of a standard psychological consultation as part of pre-surgical decision-making in high-risk women, 2) reasons for PM and reasons for postponing it, 3) the need for additional psychological interventions, and factors associated, and 4) the frequency of psychiatric/psychological treatment history.Methods: During a 30 months period, women at high risk considering PM were offered a psychological consultation. The content of these, and follow-up, consultations were analyzed.Results: Most women (70 out of 73) accepted the psychological consultation, and 81% proceeded with PM. Main reasons for undergoing PM were to reduce anxiety about cancer, and to reduce the cancer risk. Uncertainty about surgery and the need for further information were the reasons given most frequently for postponing PM. Additional psychological support was given to 31% before and 14% after PM. The uptake of additional support was significantly higher in women with a BRCA1/2 mutation. A history of psychiatric/psychological treatment was present in 36%, mainly consisting of depression and grief after death of a mother.Conclusion: The uptake-rate of the standard psychological consultation indicates a high level of acceptability of this service for women deciding about PM. Since anxiety is one of the main reasons for considering PM, and depression and grief were present in a third, a standard consultation with a psychologist for high-risk women considering PM may be indicated. This may help them arrive at an informed decision, to detect and manage psychological distress, and to plan psychological support services.

Neurotoxic and neuroprotective metabolites of kynurenine in patients with renal cell carcinoma treated with interferon-α: Course and relationship with psychiatric status (Article)

2008-10-01T00:00:00Z

Aims: Immunotherapy with interferon-α (IFN-α) is associated with psychiatric side-effects, including depression. One of the putative pathways underlying these psychiatric side-effects involves tryptophan (TRP) metabolism. Cytokines including IFN-α induce the enzyme indoleamine 2,3-dioxygenase (IDO), which converts TRP to kynurenine (KYN), leading to a shortage of serotonin (5-HT). In addition, the production of neurotoxic metabolites of KYN such as 3-hydroxykynurenine and quinolinic acid (QA) might increase and contribute to IFN-α-induced psychopathology. In contrast, other catabolites of KYN, such as kynurenic acid (KA), are thought to have neuroprotective properties. Methods: In a group of 24 patients treated with standard IFN-α for metastatic renal cell carcinoma (RCC), combined psychiatric and laboratory assessments were performed at baseline, 4 and 8 weeks, and at 6 months. Results: No psychopathology was observed, despite an increase in neurotoxic challenge as reflected in indices for the balance between neurotoxic and neuroprotective metabolites of KYN. Conclusions: The present hypothesis that a shift in the balance between neurotoxic and neuroprotective metabolites of KYN underlies the neuropsychiatric side-effects of IFN-α-based immunotherapy, is neither supported nor rejected.

Misattribution of agency in schizophrenia: An exploration of historical first-person accounts (Article)

2008-06-01T00:00:00Z

This paper provides a concise description and discussion of bottom-up and top-down approaches to misattribution of agency in schizophrenia. It explores if first-person accounts of passivity phenomena can provide support for one of these approaches. The focus is on excerpts in which the writers specifically examine their experiences of external influence. None of the accounts provides arguments that fit easily with only one of the possible approaches, which is in line with current attempts to theoretical integration.

Plasma activity of prolyl endopeptidase in relation to psychopathology during immunotherapy with IFN-α in patients with renal cell carcinoma (Article)

2008-05-01T00:00:00Z

Abnormal activity in peripheral blood of the cytosolic enzyme prolyl endopeptidase (PEP, EC 3.4.21.26, post prolyl cleaving enzyme, prolyl oligopeptidase) has been found in patients with a variety of psychiatric disorders, most consistently in mood disorders. Mood disturbance is a well-known side effect of immunotherapy with interferon-α (IFN-α). Earlier, we documented a decrease in serum PEP activity in the first 4 weeks of treatment with IFN-α. In 24 patients (16 men, 8 women, median age 60.5 years, range 47-72 years) with metastatic renal cell carcinoma (RCC), psychiatric assessment and blood sampling were performed before and at 4 and 8 weeks and at 6 months after initiation of treatment with IFN-α. No episodes of depression were observed, and the sum score and the scores on the subscales for depression and hostility of the Symptom Check List-90 (SCL-90) did not change during follow-up, whereas the anxiety scores were somewhat lower at 4 and 8 weeks compared with baseline. No change in plasma PEP activity and no relationships between change in psychiatric parameters and change in plasma PEP activity were found. As more subtle relationships between PEP activity and psychiatric status could have easily been obscured, a role for PEP in the pathophysiology of IFN-α-induced mood disturbance can neither be confirmed nor excluded.

Interferon-alpha in oncology patients: fewer psychiatric side effects than anticipated (Article)

2008-01-01T00:00:00Z

Interferon-alpha (IFN-alpha) treatment in both oncological and hepatological settings is associated with depression. If IFN-alpha treatment induces depression in high numbers, it could serve as a model for studying the pathophysiology of depression, in general. The authors therefore studied 43 oncology patients treated with standard or pegylated IFN-alpha with baseline psychiatric assessment and at regular time-points in the first 6 months of treatment. Apart from a severe depression because of brain metastases, authors observed only two clinically relevant depressive states. Contrary to findings in most of the literature, most depressive episodes in this study were self-limiting and short-lasting and were associated with either episodes of flu-like symptoms common at the start of the treatment or with concurrent psychosocial events. In the group as a whole, scores on both observer-based and self-report rating scales did not show clinically relevant changes. The results of this study indicate that IFN-alpha treatment is not suitable as a study model for depression in general.

The common sense model of self-regulation and psychological adjustment to predictive genetic testing: A prospective study (Article)

2007-12-01T00:00:00Z

This prospective study explored the contribution of illness representations and coping to cancer-related distress in unaffected individuals undergoing predictive genetic testing for an identified mutation in BRCA1/2 (BReast CAncer) or an HNPCC (Hereditary Nonpolyposis Colorectal Cancer)-related gene, based on the common sense model of self-regulation. Coping with hereditary cancer (UCL), illness representations (IPQ-R) and risk perception were assessed in 235 unaffected applicants for genetic testing before test result disclosure. Hereditary cancer distress (IES) and cancer worry (CWS) were assessed before, 2 weeks after and 6 months after result disclosure. Timeline (r = 0.30), consequences (r = 0.25), illness coherence (r = 0.21) and risk perception (r = 0.20) were significantly correlated to passive coping. Passive coping predicted hereditary cancer distress and cancer worry from pre-test (β= 0.46 and 0.42, respectively) up to 6 months after result disclosure (β= 0.32 and 0.19, respectively), Illness coherence predicted hereditary cancer distress up to 6 months after result disclosure (β= 0.24), too. The self-regulatory model may be useful to predict the cognitive and emotional reactions to genetic cancer susceptibility testing. Identifying unhelpful representations and cognitive restructuring may be appropriate interventions to help distressed individuals undergoing genetic susceptibility testing for a BRCA1/2 or a HNPCC-related mutation. Copyright

The Effects of Analgesic Prescription and Patient Adherence on Pain in a Dutch Outpatient Cancer Population (Article)

2007-11-01T00:00:00Z

Insufficient awareness of cancer pain, including breakthrough pain, inadequate analgesic prescriptions, and nonadherence contribute to inadequate cancer pain management. There are insufficient data about the contribution of each of these factors. In a cross-sectional survey among 915 adult cancer outpatients, pain was assessed by the Brief Pain Inventory. Breakthrough pain was defined as a worst pain intensity rated as "7 or more" and an average pain intensity rated as "6 or less" in patients on "around-the-clock" (ATC) analgesics. The Pain Management Index (PMI) was calculated to measure the quality of treatment. Adherence was considered inadequate when below 100% of the dose prescribed. Pain was present in 27% of patients. Worst pain was rated as moderate in 26%, and as severe in 54%. Breakthrough pain was present in 45% of patients with ATC medication. The PMI indicated inadequate treatment in 65% of patients. The proportions of patients adherent to ATC analgesics varied from 59% (tramadol) to 91% (Step 3 opioids). The management of cancer pain will benefit most from improving analgesic prescriptions and patient adherence.

Interferon-α influences tryptophan metabolism without inducing psychiatric side effects (Article)

2007-10-01T00:00:00Z

Background: Interferon-α (IFN-α) treatment is often associated with psychiatric side effects and has been found to lower the amount of tryptophan (TRP) available to the brain. The alterations in tryptophan metabolism might underlie the psychiatric side effects during treatment with IFN-α. Methods: In this study, 43 oncology patients treated with IFN-α were included. In order to study de novo depressions, depressed patients at baseline were excluded. Psychiatric evaluation comprising clinical judgment combined with a structured psychiatric interview and observer-based and self-report rating scales was performed at baseline and at 4 weeks, 8 weeks and 6 months after the start of treatment with IFN-α, and in the case of emerging psychopathology. Blood samples were drawn at the same evaluation times and assessed for concentrations of TRP, large neutral amino acids, kynurenine, 5-hydroxyindole acetic acid, neopterin and biopterin. Results: During treatment with IFN-α, several alterations in laboratory parameters occurred that were consistent with an increased degradation of peripheral TRP. Psychometric ratings revealed hardly any psychiatric changes. No consistent associations were found between changes in the laboratory assessments determined and the diverse psychiatric measures. Conclusion: In this study, IFN-α was found to alter TRP metabolism without inducing psychiatric side effects. Therefore, a possible relationship between TRP metabolism and depression was not substantiated by this study. Copyright

Case-referent comparison of cognitive functions in patients receiving haematopoietic stem-cell transplantation for haematological malignancies: Two-year follow-up results (Article)

2007-09-01T00:00:00Z

During bone marrow or haematopoietic stem-cell transplantation (HSCT), potentially neurotoxic treatments are used. Previous studies identified cognitive disturbances in patients treated with HSCT, but prospective studies with longitudinal assessment are sparse. We examined cognitive functions up to 20 months after a first baseline assessment in 101 patients undergoing HSCT and in 82 reference patients with a haematological malignancy treated with non-myeloablative cancer therapies. Baseline findings revealed no between-group differences and demonstrated mild cognitive impairments in both groups. Follow-up analyses showed no significant changes over time, though poorer performance in attention and executive function, and psychomotor function was found in HSCT patients. Our results suggest limited HSCT-related cognitive dysfunctions. Additional follow-up is necessary to assess long-term effects.

A prospective study of the impact of genetic susceptibility testing for BRCA1/2 or HNPCC on family relationships (Article)

2007-04-01T00:00:00Z

This study assessed the impact of genetic testing for cancer susceptibility on family relationships and determinants of adverse consequences for family relationships. Applicants for genetic testing of a known familial pathogenic mutation in BRCA1/2 or a HNPCC related gene (N=271) rated the prevalence and nature of changes in family relationships, familial difficulties and conflicts due to genetic testing 6 months after receiving the test result. The level of family functioning, differentiation from parents, support and familial communication style regarding hereditary cancer were assessed before receiving the test result. Genetic testing affected some family relationships in a positive way (37%), i.e. by feeling closer, improved communication and support, more appreciation of the relative and relief of negative test result. A minority reported unwanted changes in relationships (19%), problematic situations (13%) or conflicts (4%). Adverse effects comprised feelings of guilt towards children and carrier siblings, imposed secrecy and communication problems. Predictors of adverse consequences on family relationships were reluctance to communicate about hereditary cancer with relatives and disengaged-rigid or enmeshed-chaotic family functioning. Open communication between relatives should be stimulated because a lack of open communication may be an important determinant of familial adverse effects. Copyright

Family system characteristics and psychological adjustment to cancer susceptibility genetic testing: A prospective study (Article)

2007-01-01T00:00:00Z

This study examined prospectively the contribution of family functioning, differentiation to parents, family communication and support from relatives to psychological distress in individuals undergoing genetic susceptibility testing for a known familial pathogenic BRCA1/2 or Hereditary nonpolyposis colorectal cancer-related mutation. Family functioning, differentiation to parents, hereditary cancer-related family communication and perceived support from relatives were assessed in 271 participants for genetic testing before test result disclosure. Hereditary cancer distress (assessed by the Impact of Event Scale) and cancer worry (assessed by the Cancer Worry Scale) were assessed before, 1 week after, and 6 months after test result disclosure. Participants reporting more cancer-related distress over the study period more frequently perceived the communication about hereditary cancer with relatives as inhibited, the nuclear family functioning as disengaged-rigid or enmeshed-chaotic, the support from partner as less than adequate and the relationship to mother as less differentiated. Especially, open communication regarding hereditary cancer and partner support may be important buffers against hereditary cancer distress. Identifying individuals with insufficient sources of support and addressing the family communication concerning hereditary cancer in genetic counseling may help the counselee to adjust better to genetic testing.

Comparison of individuals opting for BRCA1/2 or HNPCC genetic susceptibility testing with regard to coping, illness perceptions, illness experiences, family system characteristics and hereditary cancer distress (Article)

2007-01-01T00:00:00Z

Objective: To study differences between individuals opting for genetic cancer susceptibility testing of a known familial BRCA1/2 and HNPCC related germline mutation. Methods: Coping, illness perceptions, experiences with cancer in relatives and family system characteristics were assessed in 271 applicants for genetic testing before test result disclosure. Hereditary cancer distress, worry and cancer risk perception were assessed before, 1 week after, and 6 months after disclosure. Results: Individuals from BRCA1/2 and HNPCC mutation families did not differ with regard to the number of experiences with cancer in relatives, grief symptoms, the course of cancer distress, worry and risk perception through time and most illness perceptions, coping responses and family characteristics. Individuals from BRCA1/2 families perceived hereditary cancer as more serious. They reported more frequently a passive coping style, cancer worry and a less open communication with their partner and children. Conclusion: Besides subtle differences, psychological mechanisms may be mainly identical in individuals opting for BRCA1/2 and HNPCC susceptibility testing. Practice implications: Based on our findings, using a similar counseling approach for individuals opting for BRCA1/2 or HNPCC genetic susceptibility testing is justified. In this approach, attention should be directed more to individual aspects than to the type of disorder.

Prognostic factors for hereditary cancer distress six months after BRCA1/2 or HNPCC genetic susceptibility testing (Article)

2007-01-01T00:00:00Z

This study explored predictors for hereditary cancer distress six months after genetic susceptibility testing for a known familial BRCA1/2 or HNPCC related mutation, in order to gain insight into aspects relevant for the identification of individuals needing additional psychosocial support. Coping, illness representations, experiences with cancer in relatives and family system characteristics were assessed in 271 applicants for genetic testing before result disclosure. Hereditary cancer distress was assessed prospectively up to six months after disclosure. Regression analysis revealed that the pretest level of distress, complicated grief, the number of affected first-degree relatives and strong emotional illness representations were factors that best explained hereditary cancer distress. Other significant predictors were illness coherence, passive coping, distraction seeking, being aged <13 years when a parent was affected by cancer and family communication. Individuals who may benefit from additional support may be identified before result disclosure using a short instrument assessing the relevant aspects.

The course of distress in women at increased risk of breast and ovarian cancer due to an (identified) genetic susceptibility who opt for prophylactic mastectomy and/or salpingo-oophorectomy (Article)

2007-01-01T00:00:00Z

The levels and course of psychological distress before and after prophylactic mastectomy (PM) and/or prophylactic salpingo-oophorectomy (PSO) were studied in a group of 78 women. General distress was measured through the hospital anxiety and depression scale (HADS), cancer-related distress using the impact of events scale (IES). Measurement moments were baseline (2-4 weeks prior to prophylactic surgery), and 6 and 12 months post-surgery. After PM, anxiety and cancer-related distress were significantly reduced, whereas no significant changes in distress scores were observed after PSO. At one year after prophylactic surgery, a substantial amount of women remained at clinically relevant increased levels of cancer-related distress and anxiety. We conclude that most women can undergo PM and/or PSO without developing major emotional distress. More research is needed to further define the characteristics of the women who continue to have clinically relevant increased scores after surgery, in order to offer them additional counselling.

Influence of pegylated interferon-α therapy on plasma levels of citrulline and arginine in melanoma patients (Article)

2007-01-01T00:00:00Z

The aim of this study was to evaluate the effect of pegylated interferon-alpha (PEG-IFN-α) on the plasma citrulline/arginine ratio, regarded as an index of nitric oxide (NO) synthesis, in patients with high-risk melanoma. Forty patients were randomly assigned to either PEG-IFN-α treatment (n = 22) or to observation only (control group, n = 18). The treatment group received 6 μg PEG-IFN-α/kg once a week during 8 weeks, followed by a maintenance dose of 3 μg/kg/wk. Blood was collected at different time points, plasma concentrations of citrulline and arginine were measured and the ratio of citrulline/arginine was calculated. Patients treated with PEG-IFN-α showed a significant decrease in the concentrations of citrulline and in the citrulline/arginine ratio during the whole study period, both compared to baseline values and to the control group. The data suggest that therapy with PEG-IFN-α results in a marked decrease in the synthesis of NO in melanoma patients.

Psychiatric Side Effects of Treatment with Interferon-alpha in Oncology Patients (Doctoral Thesis)

2006-02-08T00:00:00Z

Treatment with the cytokine interferon-α (IFN-α) is associated with a wide array of side effects including psychiatric side effects, most notably depressive symptoms and syndromes. In this thesis, both the somatic and the psychiatric side effects, their presumed pathophysiology, and the strategies to handle them are reviewed. Biochemical parameters possibly underlying IFN-α induced mood disorder were investigated. Treatment with IFN-α decreased tryptophan blood levels and the availability of tryptophan to the brain, possibly inducing diminished serotonin synthesis in the brain. The degradation of tryptophan to kynurenin was increased and as several of the breakdown products of kynurenin are presumed to be neurotoxic, this could contribute to psychiatric side effects. In addition, treatment with IFN-α consistently increased blood concentrations of neopterin, possibly leading to shortage of tetrahydrobiopterin, an essential co-factor in the biosynthesis of serotonin. Although concentrations of biopterin, the metabolite of tetrahydrobiopterin, did not change, the conversion of phenylalanine to tyrosine, in which tetrahydrobiopterin is also a co-factor, was diminished. Activity of monoamine oxidase (MAO) in platelets increased during therapy with IFN-α. Increased MAO activity in the brain possibly increases breakdown of serotonin. Finally, we found decreased activity of prolyl endopeptidase (PEP) during therapy with IFN-α, a enzyme possibly involved in the breakdown of psychoactive peptides. The activity of the exopeptidase dipeptidyl peptidase-IV (DPP-IV) did not change. In our clinical research, despite the changes in the aforementioned laboratory parameters, the incidence of IFN-α-induced depression was lower than expected and few clinically relevant mood disorders bearing a probable relationship with IFN-α occurred. We conclude, that treatment with the used doses of IFN-α in oncology patients is not a suitable research model into the treatment of mood disorders and that the observed changes in laboratory parameters do not induce psychiatric disorder.

Clinical experience with venlafaxine in the treatment of hot flushes in women with a history of breast cancer (Article)

2005-01-01T00:00:00Z

OBJECTIVE: To obtain practical experience with venlafaxine for hot flushes in breast cancer patients and incorporate this in a treatment protocol. METHOD: Twenty-two women with a history of breast cancer (mean age 49.2 years, range 35-65) were referred for consideration of treatment with venlafaxine for hot flushes. Patients received extensive information on treatment with venlafaxine and were advised to self-monitor the frequency of their hot flushes. RESULTS: Eight women did not start venlafaxine because they had no postmenopausal complaints, were lost to follow-up, had too low a frequency of hot flushes, or refused treatment. Eventually 14 women started venlafaxine. Two of them did not tolerate venlafaxine, four reported some effect but stopped because of side effects, two women had no effect whatsoever. Six women observed a clear ( > 50%) reduction in their hot flush frequency that was maintained at a median follow-up of 13 months. CONCLUSION: The group of patients referred for treatment was more heterogeneous and more patients dropped out because of side effects than expected. Extensive patient education, patient selection and evaluation of the treatment effect (by self-monitoring of hot flush frequency) are mandatory to avoid useless (continuation of) treatment and to prepare patients for side effects. Under these conditions, a substantial minority of patients benefit from venlafaxine.