[Delirium as a late onset manifestation of quetiapine intoxication]. / Delier als late complicatie van intoxicatie met quetiapine.

In this article we describe the developments of two patients who were hospitalized after a quetiapine overdose, subsequently developing delirium. Delirium occurred several hours after ingestion and lasted several days. Laboratory blood testing revealed a slower decline in quetiapine plasma concentration than expected when compared to the standardized half-life averages of therapeutic doses of quetiapine. The clinical state during the first hours after ingestion does not sufficiently predict further clinical outcome. The changes in pharmacokinetics due to the intoxication, so-called toxicokinetics, are the underlying cause.

Higher doses of opioids in patients who need palliative sedation prior to death: cause or consequence?

BACKGROUND: Palliative sedation (PS) is necessary in a significant percentage of patients dying on an acute palliative care unit (PCU). Common indications are terminal restlessness, pain and dyspnoea. On our PCU, terminal restlessness was the main indication for PS but pain was the most prevalent symptom during admission. Because delirium is often drug induced in terminal cancer patients and opioids are amongst the most frequently implicated drugs, we hypothesised that the underlying pain problem and its treatment might have been related to the need for sedation. PATIENTS AND METHODS: To test this hypothesis, we did a retrospective analysis on the use of medication with potential cognitive side-effects, focusing on analgesics, in 68 patients who died on the PCU after PS and 89 patients who died without PS. RESULTS: Ultimately sedated patients used opioids in significantly higher doses; they were more often treated with a rotation to another opioid and with amitriptyline. The dose of opioids used at various time points between admission and death was strongly related to the probability of PS. CONCLUSIONS: Our findings support the hypothesis that, although pain was not the main indication for PS, pain and its treatment might have been primarily related to the need for palliative sedation in this patient cohort.

The Distress Thermometer assessed in women at risk of developing hereditary breast cancer.

OBJECTIVES: The Distress Thermometer (DT) is a promising instrument to get insight into distress experienced by cancer patients. At our Family Cancer Clinic the DT, including an adapted problem list, was completed by 100 women at increased risk of developing hereditary breast cancer (mean age 45.2 years; SD: 10.5). Additionally, the women filled in either the Hospital Anxiety and Depression Scale as psychological component (n=48) or the somatic subscale of the Symptom Checklist-90 as somatic component (n=50) to identify associations with the DT-score. Further, the women filled in an evaluation form. RESULTS: The median score on the DT was 2 (range: 0-9). With regression analysis adjusted for age, the contribution of mood and somatic complaints, respectively, was investigated. The standardized regression coefficient for anxiety was 0.32 (ns), for depression 0.14 (ns) and for the somatic subscale 0.49 (p<0.001). The explained variance for anxiety and depression was 16%, and for somatic complaints 24%. The differences between the coefficients were not significant. Evaluation forms were returned by 73 women. In 50% of the cases, the physician had discussed the DT/problem list, which was appreciated by the majority of these women (80%). Sixty-two percent of the women would recommend the use of the DT for other patients. CONCLUSION: The use of the DT/problem list seems promising for the current population, and was appreciated by the majority of the women. As mood and somatic complaints did not differ significantly in explaining the experienced distress, other candidate factors need to be examined.

Plasma activity of prolyl endopeptidase in relation to psychopathology during immunotherapy with IFN-alpha in patients with renal cell carcinoma.

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-alpha (IFN-alpha). Earlier, we documented a decrease in serum PEP activity in the first 4 weeks of treatment with IFN-alpha. 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-alpha. 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-alpha-induced mood disturbance can neither be confirmed nor excluded.

Influence of pegylated interferon-alpha therapy on plasma levels of citrulline and arginine in melanoma patients.

The aim of this study was to evaluate the effect of pegylated interferon-alpha (PEG-IFN-alpha) 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-alpha treatment (n = 22) or to observation only (control group, n = 18). The treatment group received 6 microg PEG-IFN-alpha/kg once a week during 8 weeks, followed by a maintenance dose of 3 microg/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-alpha 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-alpha results in a marked decrease in the synthesis of NO in melanoma patients.

Clinical experience with venlafaxine in the treatment of hot flushes in women with a history of breast cancer.

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.

Serum activity of prolyl endopeptidase, but not of dipeptidyl peptidase IV, is decreased by immunotherapy with IFN-alpha in high-risk melanoma patients.

Immunotherapy with interferon-alpha (IFN-alpha) induces neuropsychiatric side effects, most notably depression. In hepatitis patients treated with IFN-alpha, severity of depression correlates with a decrease in serum activity of dipeptidyl peptidase IV (DPP-IV, EC 3.4.14.5), a membrane-bound protease involved in the cleavage of cytokines and neuroactive peptides. Abnormal serum activity of the cytosolic peptidase prolyl endopeptidase (PEP, EC 3.4.21.26, postprolyl cleaving enzyme, prolyl oligopeptidase) has been documented in patients with a variety of psychiatric disorders, most consistently in mood disorders. The serum activity of PEP and DPP-IV was measured before and after 4 weeks of high-dose induction treatment with IFN-alpha in 18 patients with high-risk melanoma. In this exploratory study, we show a clear decrease in the serum activity of PEP after 4 weeks of treatment with IFN-alpha. This decrease was not related to changes in hematologic parameters. In contrast, serum activity of DPP-IV did not change. Further studies focusing on a possible role of PEP in the pathophysiology of IFN-alpha-induced depression are warranted.

Psychiatric consultation and quality of decision making in euthanasia.

The role of undiagnosed psychiatric disorders in patients requesting euthanasia is an important ethical and professional issue. From June, 1997, until June, 1999, we included a psychiatric consultation as part of our standard procedure for handling euthanasia requests. Of 22 cancer patients who requested euthanasia at short notice: ten had their longstanding and well-considered wish for euthanasia granted; six were denied euthanasia because they did not have such a wish; five were denied because of psychiatric problems; and one was granted the wish despite minor psychiatric symptoms. Our findings suggest that a psychiatrist should be consulted if the treatment team has doubts about a patient's state of mind.

[Side effects of interferon alfa]. / Bijwerkingen van interferon alfa.

Interferons are a class of glycoproteins whose properties include antiviral, immunomodulatory and antiproliferative effects. Immunotherapy with interferons is used in a variety of diseases, such as haemato-oncological disorders, solid tumours, viral hepatitis and multiple sclerosis. Due to their involvement in the regulation of a large number of physiological functions, many different side effects can occur. Flu-like syndromes, gastrointestinal complaints, fatigue, pain, increased susceptibility to infections, thyroid dysfunction and psychiatric side effects occur frequently with alfa-interferon. Side effects frequently necessitate interruption and dose reduction. Severe or even life-threatening side effects are not frequent but do occur. Patient education is an important promotor of patient compliance, as are proper detection and symptomatic treatment of the side effects.

Management of psychiatric adverse events with immunotherapy with interferon-alfa.

Immunotherapy with interferon-alfa has become standard therapy in selected patients with viral hepatitis and chronic myelogenous leukemia. In addition, it is used in a variety of other diseases, both as standard therapy and in clinical trials. Its use is expected to expand in the following decade. Interferon can cause (severe) neuropsychiatric side effects. These side effects are discussed. Adequate management of these side effects is important, as is close collaboration between the oncologist and the psychiatrist. The cornerstone of management is patient education: this prevents interruption of therapy by patients who were not warned for neuropsychiatric side effects. Furthermore, patients should report in case of rapidly arising mood disorders. Interferon-alfa induced mood disorder is reported to be treatable. Three case descriptions illustrate this, but also illustrate some limits to successful treatment.