Clinical response augments NK cell activity independent of treatment modality: a randomized double-blind placebo controlled antidepressant trial.

BACKGROUND: Major depressive disorder (MDD) has been associated with alterations in immune function. Suppression of natural killer (NK) cell activity (NKCA) reliably characterizes immunological alterations observed in MDD. Antidepressant pharmacotherapy has been associated with modulation of NKCA. Previous investigations into antidepressant modulation of NKCA have not employed randomized double-blind placebo controlled designs. Thus, it is unknown whether treatment-associated changes in immune function are due to drug, placebo, or spontaneous remission effects. The present investigation examined the effect of antidepressant treatment on NKCA utilizing a randomized double-blind placebo controlled experimental design. METHOD: Patients (N = 16) met DSM-IV criteria for MDD and were randomly assigned to drug (N = 8; citalopram, 20 mg/day) or placebo (N = 8) under double-blind conditions. Severity and pattern of depressive symptoms were assessed by the Hamilton Depression Rating Scale (HDRS). NK cell function was measured using a standard chromium-release assay and NK cell number assessed by flow cytometry. HDRS scores, NK cell function, and NK cell numbers were collected at 0, 1, 2 and 4 weeks of treatment. RESULTS: Clinical response was associated with augmented NKCA independent of treatment condition. Failure to respond to treatment resulted in significantly reduced NKCA over treatment interval. CONCLUSIONS: The present results suggest that alterations in the depressive syndrome, regardless of therapeutic modality, may be sufficient to modulate NKCA during antidepressant trials and thus may significantly impact on co-morbid health outcomes in MDD.

3,4-dihydroxyphenylacetaldehyde: a potential target for neuroprotective therapy in Parkinson's disease.

The simplest explanation for the selective loss of substantia nigra (SN) dopamine (DA) neurons in Parkinson's disease (PD) is that DA or a metabolite is neurotoxic. Recently, a series of investigations implicate the MAO metabolite of DA, 3,4-dihydroxyphenylacetaldehyde (DOPAL), as the critical endogenous toxin which triggers DA neuron loss in PD: 1. Hereditary PD contains mutations in the gene for alpha-synuclein (alpha-syn). Investigations implicate a DA metabolite as mediator of alpha-syn neurotoxicity, and DOPAL is 1000-fold more toxic than DA in vivo. 2. A deficit in mitochondrial complex I is found in PD SN. Inhibition of complex I causes increases in DOPAL levels and death of DA neurons in vitro and in vivo. 3. L-DOPA, the precursor of DA, which is used to treat PD, is toxic and contributes to the progression of PD. L-DOPA-treated rats have an 18-fold increase in striatal DOPAL. 4. Free hydroxyl radicals (.OH) trigger aggregation of alpha-syn to its toxic form. DOPAL with H(2)O(2) generates.OH radicals. These investigations provide several therapeutic strategies to limit DOPAL toxicity and progression of PD: 1. Delaying the start of L-DOPA therapy by early use of DA receptor agonists, which may also be free radical scavengers, limits the amount of DOPAL formed from L-DOPA. 2. Nonspecific MAO inhibitors may more effectively decrease production of DOPAL from DA than MAO-B inhibitors. 3. Newer more potent and targeted free radical scavengers could block DOPAL toxicity. 4. Coenzyme Q(10) increases complex I activity and nicotine adenine dinucleotide (NAD) synthesis, and thereby could enhance DOPAL catabolism by aldehyde dehydrogenase, which uses NAD as a cofactor. 5. DA uptake blockers could be used to limit intraneuronal DOPAL production. 6. Tauroursodeoxycholic acid, an inhibitor of apoptosis shown to be effective in models of Huntington's disease, may also prove effective in blocking DOPAL toxicity in PD. 7. Agents which block aggregation of alpha-syn should limit DOPAL toxicity.

Exploring treatment alternatives: weekly dosing of fluoxetine for the continuation phase of major depressive disorder.

Antidepressant medications are typically taken on a daily basis owing to both tradition and the pharmacokinetics of these agents. Because fluoxetine and its primary metabolite norfluoxetine have long half-lives and flat dose-response curves, we examined the tolerability of a weekly dose and its equivalence to daily dosing during the continuation phase of treatment for major depressive disorder (MDD). Open-label treatment with 20 mg of fluoxetine daily for 7 weeks began with 114 subjects. Subsequently, 70 subjects who met criteria for response were randomly assigned in a double-blind design to 1 of 3 treatment groups (20 mg of fluoxetine daily [N = 21], 60 mg of fluoxetine weekly [N = 28], or placebo [N = 21]) and followed for 7 weeks. No statistically significant differences were observed in several clinical measures. Tolerability in the 3 groups was similar; there was no difference in dropout rates or adverse events. Hence, weekly dosing of fluoxetine appears to be well tolerated and possibly as effective as daily dosing in the treatment of MDD. It is proposed that less frequent dosing could potentially benefit patients by enhancing adherence and minimizing the risk of side effects and drug-drug interactions.

3,4-Dihydroxyphenylacetaldehyde and hydrogen peroxide generate a hydroxyl radical: possible role in Parkinson's disease pathogenesis.

3,4-Dihydroxyphenylacetaldehyde (DOPAL) and 3,4-dihydroxyphenylglycolaldehyde (DOPEGAL), the monoamine oxidase (MAO) metabolites of dopamine (DA) and norepinephrine (NE), respectively, are toxic to catecholamine (CA) neurons in vitro and in vivo. DOPEGAL generates a free radical and activates mitochondrial permeability transition, a mechanism implicated in neuron death. To determine if DOPAL and other DA metabolites generate the hydroxyl radical in the presence of H(2)O(2), we used HPLC-EC to detect salicylate hydroxylation products. To determine the relative reducing capacity of DOPAL and DOPEGAL we used cyclic voltammetry to measure their reduction potentials. Results indicate that DOPAL, but not DOPEGAL, DA or other DA metabolites, generates hydroxyl radicals. Atomic absorption spectroscopy and heavy metal screening indicate that this result is not due to contamination of DOPAL with iron or other heavy metals. DOPAL reduction potential (161 mV) is lower than that of DOPEGAL (235 mV). DOPAL is present in human substantia nigra. The implications of these findings to CA neuronal death in degenerative brain diseases are discussed.

An open-label trial of tomoxetine in pediatric attention deficit hyperactivity disorder.

OBJECTIVE: To collect pilot data assessing the safety, tolerability, and efficacy of tomoxetine, a nonstimulant norepinephrine enhancer, in pediatric attention deficit hyperactivity disorder (ADHD). METHODS: An open-label trial of tomoxetine in pediatric ADHD was conducted as part of a multisite clinical trial. Following a baseline assessment, an ascending dose titration was completed during 10 weekly visits. RESULTS: Ten subjects were enrolled at baseline, with eight completing the study. Seven of the eight remaining subjects met efficacy criteria. Significant decreases in symptom severity ratings by parents and study investigators were found. The medication was well tolerated, with transient appetite suppression the most frequently reported side effect. However, subjects' weights remained stable across study visits. DISCUSSION: These preliminary findings suggest that tomoxetine may hold promise as a treatment for pediatric ADHD.

Levels of monocyte reactive oxygen species are associated with reduced natural killer cell activity in major depressive disorder.

Major depressive disorder (MDD) is associated with reductions in natural killer cell activity (NKCA), however the mechanism(s) mediating reduced NKCA in MDD has yet to be determined. In light of evidence that MDD is associated with an inflammatory immune response, we propose that reactive oxygen species (ROS), generated by inflammatory leukocytes (monocytes and/or neutrophils), may mediate the suppression of NKCA in MDD. Intracellular levels of monocyte ROS were significantly associated with reductions in NKCA in outpatients (n = 15) diagnosed with MDD. Sleep disturbance was also significantly correlated with reductions in NKCA. Elevated levels of ROS may be an additional characteristic of a subset of depressed patients in whom an inflammatory response persists and elevations in ROS may, in part, mediate the associations observed between MDD, cardiovascular disease, and cancer.

Gambling as a social activity of older adults.

A significant number of senior citizens (aged 65+) spend their leisure time in gambling casinos in this country. For some older adults eager for a stimulating social outlet, casino gambling can become a virulent and destructive addiction. While prevalence studies have examined the incidence of problem gambling in other age groups, little attention has been paid to the impact of casino gambling on older adults. This study investigated the prevalence of casino gambling as a social activity for active senior citizens (aged 65+). Activity directors from residential and assisted-care facilities as well as from senior and retirement centers completed mailed surveys of eleven different types of social activities available to older adults. Results of the survey of activity directors found bingo the most highly frequented on-location-type social activity and casino gambling the most highly frequented day-trip-type social activity for 6,957 active senior citizens represented in the activity directors' survey. On average, 16 percent of the senior citizens were reported by the activity directors to have taken part in facility-sponsored trips to the casino on at least a once-a-month basis. In addition, the casinos themselves had offered additional gambling day-trips to 66 percent of the facilities, which were accepted in 58 percent of the cases. These findings suggest the need for greater awareness of the impact casino gambling may have on senior citizens in this country.

Selective dopaminergic vulnerability: 3,4-dihydroxyphenylacetaldehyde targets mitochondria.

Parkinson's disease (PD) is a major cause of age-related morbidity and mortality, present in nearly 1% of individuals at ages 70-79 and approximately 2.5% of individuals at age 85. L-DOPA (L-dihydroxyphenylalanine), which is metabolized to dopamine by dopa decarboxylase, is the primary therapy for PD, but may also contribute to disease progression. Association between mitochondrial dysfunction, monoamine oxidase (MAO) activity, and dopaminergic neurotoxicity has been repeatedly observed, but the mechanisms underlying selective dopaminergic neuron depletion in aging and neurodegenerative disorders remain unclear. We now report that 3,4-dihydroxyphenylacetaldehyde (DOPAL), the MAO metabolite of dopamine, is more cytotoxic in neuronally differentiated PC12 cells than dopamine and several of its metabolites. In isolated, energetically compromised mitochondria, physiological concentrations of DOPAL induced the permeability transition (PT), a trigger for cell death. Dopamine was > 1000-fold less potent. PT inhibitors protected both mitochondria and cells against DOPAL. Sensitivity to DOPAL was reduced > or = 30-fold in fully energized mitochondria, suggesting that mitochondrial respiration may increase resistance to PT induction by the endogenous DOPAL in the substantia nigra. These data provide a potential mechanism of action for L-DOPA-mediated neurotoxicity and suggest two potentially interactive mechanisms for the selective vulnerability of neurons exposed to dopamine.

Catecholamine monoamine oxidase a metabolite in adrenergic neurons is cytotoxic in vivo.

3,4-Dihydroxyphenylglycolaldehyde is the monoamine oxidase-A metabolite of two catecholamine neurotransmitters, epinephrine and norepinephrine. This aldehyde metabolite and its synthesizing enzymes increase in cell bodies of catecholamine neurons in Alzheimer's disease. To test the hypothesis that 3,4-dihydroxyphenylglycolaldehyde, but not epinephrine or its major metabolite 4-hydroxy-3-methoxyphenylglycol, is a neurotoxin, we injected 3,4-dihydroxyphenylglycolaldehyde onto adrenergic neurons in the rostral ventrolateral medulla. Injections of epinephrine or 4-hydroxy-3-methoxyphenylglycol were made into the same area of controls. A dose response and time study were performed. Adrenergic neurons were identified by their content of the epinephrine synthesizing enzyme, phenylethanolamine N-methyltransferase, immunohistochemically. Apoptosis was evaluated by in situ terminal deoxynucleotidyl-transferase mediated dUTP nick end label staining. Injection of 3,4-dihydroxyphenylglycolaldehyde in amounts as low as 50 ng results in loss of adrenergic neurons and apoptosis after 18 h. The degree of neurotoxicity is dose and time dependent. Doses of 3,4-dihydroxyphenylglycolaldehyde 10-fold higher produce necrosis. Neither epinephrine nor 4-hydroxy-3-methoxyphenylglycol are toxic. A 2.5 microg injection of 3,4-dihydroxyphenylglycolaldehyde is toxic to cortical neurons but not glia. Active uptake of the catecholamine-derived aldehyde into differentiated PC-12 cells is demonstrated. Implications of these findings for catecholamine neuron death in neurodegenerative diseases are discussed.

Frontotemporal dementia: a different kind of dementia.

Frontotemporal dementia (FTD) is an umbrella term for a number of uncommon illnesses, including Pick's disease, which affect the frontal and/or temporal lobes of the brain and produce a dementia syndrome that is quite characteristic but unfamiliar to most clinicians. It is the third most common cause of cortical dementia. An overview of clinical manifestations, diagnosis, and management of FTD is provided with some specific information in relation to Pick's disease and a case example. Caregivers, in particular, need the education and support that could be provided by informed nurses.

Medication-induced dystonias in nine patients with dementia.

Evidence from previous studies of neuroleptic side effects suggests that acute dystonic reactions are rare in elderly patients. The authors report 9 cases of dystonic reactions in patients with dementia following the initiation of antipsychotic medication. The cases are important in documenting that drug-induced dystonias do occur in patients with dementia, that risperidone appears to have contributed to dystonia among elderly patients, and that the categorization of dystonic reactions needs further clarification.

Weekly dosing of fluoxetine for the continuation phase of treatment of major depression: results of a placebo-controlled, randomized clinical trial.

Fluoxetine (FLX) has a unique pharmacokinetic profile. Its major metabolite, norfluoxetine (NFLX), possesses FLX's antidepressant efficacy and a half-life of 7 to 15 days, suggesting the possibility of nonstandard dosing strategies. This study examined the tolerability of a weekly dose and its equivalence to daily dosing of FLX for the continuation phase of treatment for major depressive disorder (MDD). One hundred fourteen subjects initially received open-label treatment with 20 mg of FLX daily for 7 weeks. Subsequently, 70 subjects with a score on the Hamilton Rating Scale for Depression (HAM-D) of 12 or less were randomly assigned in a double-blind design to one of three treatment groups: 20 mg FLX daily (N = 21), 60 mg FLX weekly (N = 28), or placebo (N = 21) and were followed for 7 weeks. HAM-D scores and blood levels of FLX and NFLX were analyzed using a repeated-measures analysis of variance. During the double-blind phase, blood levels for both FLX and NFLX differed across the treatment groups, yet no statistically significant difference in HAM-D scores was observed. There was no difference in the dropout rate across the groups. Subjects could not correctly identify the treatment group into which they were assigned. Weekly dosing of FLX seems to be well tolerated and possibly as effective as daily dosing in maintaining the therapeutic response in subjects with MDD.

Late life gambling: the attitudes and behaviors of older adults.

For a significant number of retired older adults (aged 65+), gambling has become a new form of recreation and entertainment. While prevalence studies have examined the incidence of problem gambling in other age groups, little research attention has been paid to the impact of gambling on older adults since the increase in availability and accessibility of legalized gambling within the last ten years. This study investigated the prevalence of problem gambling behaviors (SOGS-R), depression (GDS-15), levels of life satisfaction (SWLS), and motivations for gambling among older adults. A total of 315 older adults completed the study questionnaire and were grouped and analyzed according to those sampled from gambling venues and those from within the community. Results of the study found the most frequent accession and spending on several types of gambling occurred among older adults who were sampled at gambling venues. Older adults who were sampled at gambling venues were also found more likely to have higher levels of disordered gambling than older adults from the community, as measured by the SOGS-R. Relaxation, boredom, passing time, and getting away for the day were also the most likely reported motivations for the older adults who were gambling patrons. These findings provide an initial profile of older adults and their attitudes, motivations and gambling behaviors.

Quantitation of 3,4-dihydroxyphenylacetaldehyde and 3, 4-dihydroxyphenylglycolaldehyde, the monoamine oxidase metabolites of dopamine and noradrenaline, in human tissues by microcolumn high-performance liquid chromatography.

We recently described the chemical synthesis of 3, 4-dihydroxyphenylacetaldehyde and 3,4-dihydroxyphenylglycolaldehyde, the monamine oxidase metabolites of dopamine and noradrenaline, respectively. We demonstrated the neurotoxicity of these compounds. Catecholamine nerve cells which synthesize these aldehydes die in degenerative brain diseases, such as Parkinson's and Alzheimer's. Here we describe a sensitive method for separating these catecholaldehydes from catecholamines and their other oxidative and methylated metabolites by microcolumn high-performance liquid chromatography with electrochemical detection. We then quantitate catecholamines and their major metabolites in human brain, plasma, and urine. The method can be used to determine the role of these catecholaldehydes in human disease.

Self-injurious behavior in elderly patients with dementia: four case reports.

Self-injurious behavior (SIB) is a polymorphous and poorly understood phenomenon, probably representing the final common pathway arising from a variety of etiologies. SIB is a clinical problem that affects elderly patients, but has received little attention. Although the specific prevalence rates of SIB in elderly patients with dementia is unknown, the lack of data is striking, considering the frequency with which geriatric psychiatrists may be consulted for these and related behavioral problems. The authors present four cases of elderly patients with SIB and dementia who responded favorably to psychopharmacologic treatment.