Methylphenidate therapy improves cognition, mood, and function of brain tumor patients.

PURPOSE: Patients with malignant glioma develop progressive neurobehavioral deficits over the course of their illness. These are caused both by the effects of the disease and the effects of radiation and chemotherapy. We sought to determine whether methylphenidate treatment would improve these patients' neurobehavioral functioning despite their expected neurologic deterioration. PATIENTS AND METHODS: Thirty patients with primary brain tumors underwent neuropsychologic assessment before and during treatment with methylphenidate. Ability to function in activities of daily living and magnetic resonance imaging (MRI) findings were also documented. Patients were assessed on 10, 20, and 30 mg of methylphenidate twice daily. RESULTS: Significant improvements in cognitive function were observed on the 10-mg twice-daily dose. Functional improvements included improved gait, increased stamina and motivation to perform activities, and in one case, increased bladder control. Adverse effects were minimal and immediately resolved when treatment was discontinued. There was no increase in seizure frequency and the majority of patients on glucocorticoid therapy were able to decrease their dose. Gains in cognitive function and ability to perform activities were observed in the setting of progressive neurologic injury documented by MRI in half of the subjects. CONCLUSION: This study demonstrated improved patient function in the setting of a progressive neurologic illness. Methylphenidate should be more widely considered as adjuvant brain tumor therapy.

Pattern of neurobehavioral deficits associated with interferon alfa therapy for leukemia.

We evaluated the neuropsychological and personality profiles of 25 patients with chronic myelogenous leukemia treated with interferon alfa (IFN-alpha). This group of persons performed well below expectation on tests of cognitive speed, verbal memory, and executive functions. Personality changes included depression, increased somatic concern, and stress reactions. A control group of leukemia patients not treated with IFN-alpha had significantly better cognitive speed and mood. The pattern of cognitive and personality changes in patients receiving IFN-alpha is highly suggestive of frontal-subcortical brain dysfunction.

Mood and cognitive side effects of interferon-alpha therapy.

The central nervous system side effects associated with interferon-alpha (IFN-alpha) therapy, including depression and cognitive changes, can compromise otherwise effective immunotherapy. The term "depression" has multiple meanings ranging from a feeling of sadness to a neuropsychiatric disorder with defined diagnostic criteria. A syndrome of mood disturbance with memory impairment, cognitive slowing, and impaired executive function is common with IFN-alpha therapy and is consistent with mild subcortical dementia. Cognitive deficits and mood disorder may occur independently, and in some cases depression is a reactive phenomenon. Risk factors for development of IFN-alpha neurotoxicity include duration of treatment, high-dose therapy, and prior cranial irradiation or neurologic illness. Past or current psychiatric illness also may put the patient at risk. Subtypes of major depression are associated with neuroendocrine and neurochemical alterations that are consistent with the observed activities of IFN-alpha. This may provide insight into the etiology of IFN-alpha neurotoxicity, as well as possible interventions. Assessment of the neuropsychiatric status of patients treated with IFN-alpha should be a standard of care. Possible pharmacologic interventions to decrease the neurotoxicity associated with IFN-alpha therapy include antidepressants, psychostimulants, and opioid antagonists. Preliminary clinical and research experience suggests that it is possible to effectively palliate IFN-alpha toxicity.

Managing the neuropsychiatric adverse effects of interferon treatment.

Patients who receive interferons are vulnerable to a wide variety of neuropsychiatric adverse effects which can seriously compromise otherwise effective therapy. The nature and severity of the adverse effects are, in part, dose dependent, though there is significant variability. Effective treatment of interferon adverse effects is hindered by the absence of an identified mechanism of toxicity and lack of controlled intervention trials. Successful management of adverse effects is facilitated by a multimodal approach, starting with pre-treatment screening and discussion. Behavioural techniques help maintain daily function. Dose reduction or drug holidays may be required. Pharmacological treatment is based largely on clinical experience, though formal studies are underway. Familiarity with several classes of psychotropic medications is required, including antidepressants, anxiolytics, antipsychotics and psychostimulants. Together, these interventions may be used to reduce severity of interferon behavioural adverse effects to tolerable levels.

Studies with [11C]alprazolam: an agonist for the benzodiazepine receptor.

We have built a system for the synthesis of high specific activity carbon-11 alprazolam (Xanax), a high affinity agonist for the benzodiazepine receptor. The system produces 30-40 mCi of the compound with a specific activity of > 12,000 Ci per millimole. Using this compound we have performed PET studies on 6 normal subjects and studied the cerebral influx and efflux of the compound. The uptake in the brain was low, approx. 1% of the administered dose. However, the levels of the compound in the circulation at early time points are heavily affected by the specific activity of the tracer, i.e. when pharmacologically active doses are used as blocking doses the concentration of radioactive material is higher in the circulation and more material enters the brain. We attribute this to a depot effect where the compound is trapped in saturatable sites in an organ, probably the lungs, and is slowly released over time. In the presence of blocking doses of agonist, the compound washes out of the brain more quickly suggesting that some blockade of the receptors is occurring. However, the pharmacological activity of the compound does not permit the administration of enough material to ensure complete receptor blockade. The compound shows definite signs of acting as a receptor binding ligand but the unusual pharmacokinetics complicate the interpretation of the data.

A community approach to the prevention of dental disease in the children of developing countries.

Even in developed Western countries the ready availability of sophisticated restorative dentistry has been relatively unsuccessful in reducing the prevalence of dental disease. It is therefore totally wrong to seek to impose a similar structure of dental care in the developing countries with their shortages of wealth, communications and trained personnel. Instead, the emphasis must be on education and the application of preventive methods by relatively simply trained personnel working with the support and under the guidance of a few fully trained dentists. The establishment of a dental service in the developing countries must contain the following three elements. First, the undertaking of a nationwide survey of the prevalence of dental disease. Next the establishment of training schools in each ethnic area where dental surgeons, dental therapists and dental assistants can be recruited and trained. Lastly, the recruitment and training of local instructors in dental health to work in their own schools, villages and districts, concerned with the supervision of oral hygiene, fluoride mouthrinsing and diet. This scheme is based on the principle of self help through locally recruited and trained personnel and the encouragement of community pride in positive dental health.

Cognitive and mood disturbance as causes and symptoms of fatigue in cancer patients.

Fatigue, cognitive dysfunction, and depression are very common in cancer patients. A relationship among the three entities is recognized but poorly understood. Factors that contribute to this poor understanding are the subjective nature of the symptoms, multiple potential causes, and a lack of reliable assessment tools. An understanding of fatigue in cancer patients may benefit from studies of chronic fatigue syndrome (CFS) and other nonmalignant diseases indicating that cognitive impairment varies with physical and mental fatigue, and that symptoms of depression experienced by patients with physical illnesses and primary mood disorders are qualitatively different. The multidimensional nature of fatigue suggests that interventions should be patient-specific. They could be related to lifestyle or involve the use of specific behavioral or pharmacologic therapies. As is the case with depression and cognitive disorders, targeted interventions against cancer-related fatigue will benefit from a better understanding of its potential biologic causes. Consideration of cognitive dysfunction and depression complicates the understanding of cancer-related fatigue; however, it provides opportunities to assist patients who must deal with this serious problem.

Treatment of neurotoxic side effects of interferon-alpha with naltrexone.

Interferon-alpha (IFN-alpha) has potential dose-limiting neurotoxic side effects when used in cancer therapy. The nature of this neurotoxicity is speculative, and there is no definitive treatment. Because animal studies suggest that IFN-alpha acts at opioid receptor sites, we gave naltrexone, a long-acting opioid antagonist, to 9 patients who had hematological malignancies and who suffered from IFN-alpha side effects. Seven of these patients experienced complete or moderate relief of side effects. Five of the patients tested before and during naltrexone treatment showed improvement of cognitive functioning. Two patients could not tolerate naltrexone side effects. This study suggests an intervention against IFN-alpha side effects and provides support for the role of opioid receptor interaction in IFN-alpha neurotoxicity.

Methylphenidate in the treatment of neurobehavioral slowing associated with cancer and cancer treatment.

Psychostimulants used in the treatment of psychiatric conditions, including depression, alleviate some of the observed psychomotor retardation. We describe 3 patients with impairments of arousal and psychomotor speed secondary to tumor-related organic brain dysfunction who benefited from stimulant therapy.

Manic episodes in two patients treated with interferon alpha.

The authors report the assessment of 2 patients on interferon alpha (IFN-alpha) therapy for chronic myelogenous leukemia who developed manic symptoms long after IFN-alpha therapy had been initiated. These cases suggest that chronic IFN-alpha therapy may be associated with vulnerability for developing overt psychiatric symptoms, particularly in cases where the patient is experiencing psychosocial stress, and that the current definition of persistent adverse effects of IFN-alpha should be broadened to include the occurrence of manic episodes.

Reversible neurotoxicity of interleukin-2 and tumor necrosis factor: correlation of SPECT with neuropsychological testing.

A 41-year-old man developed subacute neurotoxicity associated with interleukin-2 and tumor necrosis factor therapy for metastatic renal cell carcinoma. Cognitive deficits revealed on neuropsychological testing and frontal lobe perfusion deficits revealed on SPECT resolved after 1 month. Findings suggest possible neuroanatomic and physiologic substrates of cytokine neurotoxicity.

A retrospective study of the psychiatric management and outcome of delirium in the cancer patient.

This report describes the evaluation and treatment of delirium in the cancer patient in a major comprehensive cancer center. Ninety consecutive cases of delirium seen by the inpatient psychiatry consultation/liaison service were analyzed in a retrospective fashion to evaluate demographic information, alcohol use, central nervous system disease, coexisting medical disease, and past psychiatric history. Delirium cases were divided into hyperalert, hypoalert, and mixed subtypes. For these three subtypes, medication profiles including dose of medication, duration of delirium, outcome, and the venue where the delirium began were also evaluated. The hyperalert subtype of delirium was the commonest type observed (71%) and had the shortest duration (P < 0.0001) and best outcome (P < 0.001). The patients with a hyperalert delirium subtype were treated with the least amount of haloperidol (P < 0.0001). Patients were delirious for longer when the delirium began in the intensive-care units (P < 0.04). In general, patients who received no haloperidol experienced delirium of longer duration (P < 0.02) than those receiving haloperidol. Since the data represent patients who were referred for psychiatric treatment, this may explain the increased number of hyperalert deliriums and, therefore, the generalizability of the results is limited. Delirium in the cancer patient is particularly problematic given the coexisting medical problems these patients experience. Because the outcome of delirium is better when the duration is shorter, it is important for clinicians to be sensitive to early symptoms so that treatment can be implemented faster, leading to less morbidity and mortality.

A prospective study of the incidence and open-label treatment of interferon-induced major depressive disorder in patients with hepatitis C.

Interferon (IFN) therapy has been associated with the development of Major Depressive Disorder (MDD) when given to patients with hepatitis C (HCV). The incidence, time course, risk factors, and treatment of IFN-induced MDD are poorly understood. The objectives of the present study were to determine the incidence of IFN-induced MDD, as well as to determine the efficacy of open-label antidepressant treatment, in particular selective serotonin reuptake inhibitors (SSRIs) for IFN-induced MDD. Thirty-nine HCV patients on IFN therapy were monitored weekly using the Beck Depression Inventory (BDI). Those who became depressed were treated with citalopram, a SSRI antidepressant. Main outcome measures included the incidence of IFN-induced MDD, as well as response rates to antidepressants in those patients who developed IFN-induced MDD. Our results showed that 13 of 39 patients (33%) developed IFN-induced MDD. There were no differences in age, gender, past history of MDD, or substance use between those who became depressed and those who did not. However, there were significantly fewer African American patients in the depressed group. Patients who developed IFN-induced MDD were on IFN therapy for an average of 12.1 weeks prior to the development of MDD. Eleven of 13 patients (85%) were responsive to antidepressant treatment. We conclude that IFN-induced MDD is common in HCV patients. Health care providers should follow IFN-treated HCV patients for the development of MDD, particularly between the 2nd and 5th months of IFN therapy. SSRIs, in particular citalopram, are an effective treatment for IFN-induced depression in HCV patients.