Peter T. Loosen

Cognitive Therapy and Pharmacotherapy for Depression.

Cognitive therapy (CT) for depression has generated considerable interest in recent years. Comparisons with tricyclic pharmacotherapy in nonbipolar outpatients have suggested that (a) CT may be roughly comparable in the treatment of the acute episode: (b) combined CT-pharmacotherapy does not appear to be clearly superior to either modality (although indications of potential enhancement do exist to justify additional studies with larger samples), and (c) treatment with CT during the acute episode (either alone or with medications) may reduce the risk of subsequent relapse following termination. Nonetheless, for a variety of reasons (e.g., limitations in study design and execution, inadequate design power, and possible differential retention), these conclusions can be considered only suggestive at this time. More than a decade after the publication of the first controlled study involving CT, the approach remains a promising, but not adequately tested, alternative to pharmacotherapy in the treatment of depression.

Individual differences in repressive-defensiveness predict basal salivary cortisol levels.

Prior studies assessing the relation between negative affective traits and cortisol have yielded inconsistent results. Two studies assessed the relation between individual differences in repressive-defensiveness and basal salivary cortisol levels. Experiment 1 assessed midafternoon salivary cortisol levels in men classified as repressors, high-anxious, or low-anxious. In Experiment 2, more rigorous controls were applied as salivary cortisol levels in women and men were assessed at 3 times of day on 3 separate days. In both studies, as hypothesized, repressors and high-anxious participants demonstrated higher basal cortisol levels than low-anxious participants. These findings suggest that both heightened distress and the inhibition of distress may be independently linked to relative elevations in cortisol. Also discussed is the possible mediational role of individual differences in responsivity to, or mobilization for, uncertainty or change.

Preferential cerebrospinal fluid acetylcholinesterase inhibition by rivastigmine in humans

This study sought to examine the feasibility of prolonged assessment of acetylcholinesterase (AChE) activity in the cerebrospinal fluid (CSF) of volunteers and to test the hypothesis that rivastigmine (ENA-713; Exelon, Novartis Pharma AG, Basel, Switzerland) selectively inhibits AChE in CSF in humans at a dose producing minimal inhibition of the peripheral enzyme. Lumbar CSF samples were collected continuously (0.1 mL x min(-1)) for 49 hours from eight healthy volunteers who took either placebo or a single oral dose of rivastigmine (3 mg). CSF specimens and samples of blood cells and blood plasma were analyzed at intervals for rivastigmine and its metabolite NAP 226-90 ([-] [3-([1-dimethylaminolethyl)-phenol]), erythrocyte AChE activity, CSF AChE activity, and plasma and CSF butyrylcholinesterase (BuChE) activity. Safety evaluations were performed 23 hours after drug dosing and at the end of the study. Evaluable data were obtained from six subjects. The mean time to maximal rivastigmine plasma concentration (tmax) was 0.83 +/- 0.26 hours, the mean maximal plasma concentration (Cmax) was 4.88 +/- 3.82 ng x mL(-1), the mean plasma area under the concentration versus time curve (AUC0-infinity) was 7.43 +/- 4.74 ng x hr x mL(-1), and the mean plasma t1/2 was 0.85 +/- 0.115 hours. The concentration of rivastigmine in CSF was lower than the quantification limit for assay (0.65 ng x mL(-1)), but NAP 226-90 reached a mean Cmax of 3.14 +/- 0.57 ng x mL(-1). Only minimal inhibition of erythrocyte AChE activity (approximately 3%) was observed. Inhibition of AChE in the CSF after rivastigmine administration was significantly greater than after placebo for up to 8.4 hours after the dose and was maximal (40%) at 2.4 hours. Plasma BuChE activity was significantly lower after rivastigmine than after placebo, but this was not clinically relevant. BuChE activity in CSF was significantly lower after rivastigmine than after placebo for up to 3.6 hours after dosing, but this difference was not sustained. This study confirms the feasibility of using continuous measurement of AChE activity in CSF over prolonged periods, that rivastigmine markedly inhibits CSF AChE after a single oral dose of 3 mg, and that the inhibition of central AChE is substantially greater than that of peripheral AChE or BuChE.

Facial expression in schizophrenia

Recent empirical studies have found that schizophrenics exhibit diminished observable facial expressivity in response to emotional stimuli (e.g., Berenbaum and Oltmanns 1992; Kring et al 1993; Kring and Neale 1996) yet report experiencing similar levels of emotion as their normal counterparts; however, it remains unclear whether schizophrenics are completely unexpressive, or if they exhibit more subtle, unobservable facial muscle activity that cannot be seen by observers. Additionally, the diminished facial expressiveness found in schizophrenia may be a function of affective flattening, a side effect of medication (akinesia), or both (Blanchard and Neale 1992). The present study sought to extend previous findings of emotional responding in schizophrenics in two ways. First, because schizophrenics exhibit very little observable facial expressivity, a more sensitive measure of facial expression, facial electromyographic (EMG) activity, was recorded during the presentation of emotional films. Second, to examine more closely the effects of medication on facial expressivity, a within subjects design was employed such that all patients were tested at two time points (approximately six months apart): when they were taking neuroleptic medication and when they were medication free. The present article presents preliminary results from an ongoing longitudinal study of affective response in schizophrenia.

The effects of antidepressants on the thyroid axis in depression

Thirty-nine patients with major depression were studied to determine the differential effects of desipramine (DMI) and fluoxetine (FLU) on thyroid hormones. Twenty-six percent showed some abnormality in baseline thyroid hormone levels. There were no demonstrable differences for any of the thyroid indices from baseline to the 3- or 6-week samples for the total group or for either drug by repeated measures analysis of variance. There was a significant group by time interaction for total thyroxine (TT4) between the drug treatment groups, which was caused by a small but significant increase in TT4 in the DMI sample. Correlations were performed between the change in hormones over the 6 week period and treatment response. There was a significant association between a decline in triiodothyronine (T3) levels and response to FLU but not DMI. The implications of these findings for the pathophysiology of depression and antidepressant drug mechanisms are discussed.

Effects of thyroid hormones on central nervous system in aging

Support for the many relationships between thyroid hormones and brain function comes from both laboratory and clinical studies. Studies in laboratory animals provide convincing evidence for a neuroregulatory role of thyroid hormones in the brain, suggesting that they may affect behavior. This notion is supported by human studies which have revealed that the effects of thyroid hormones on brain function are most important during the development and maturation of the brain; thereafter, age does not seem to critically affect brain-thyroid hormone relationships.

Pituitary responses to thyrotropin releasing hormone in depressed patients: A review

Numerous studies show that most depressed patients show abnormal pituitary responses to challenge by intravenous injection of thyrotropin releasing hormone (TRH). Some patients show after TRH diminished thyroid stimulating hormone (TSH) release, some show unexpected growth hormone release; prolactin release may be increased or decreased. The diminished TSH release is the most widely reported finding. It cannot be accounted for by primary changes in the pituitary or thyroid glands. Interference with TRH-induced TSH release by elevated cortisol may account for some observations, but this possibility has not been studied. The present data provide additional evidence that in depression there is often a disruption of hypothalamic regulatory function.

Uncoupling of serotonergic and noradrenergic systems in depression: Preliminary evidence from continuous cerebrospinal fluid sampling

We used the technique of continuous cerebrospinal fluid (CSF) sampling to test the following hypotheses regarding CNS monoaminergic systems in depression:(1) absolute concentrations of the informational substances tryptophan and 5‐hydroxyindoleacetic acid (5‐HIAA) are altered in the CNS of depressed patients (2) abnormal rhythms of tryptophan and/or 5‐HIAA, or defective conversion of tryptophan to serotonin (5HT), exist in the CNS of depressed patients, and (3) the relationship between the CNS 5HT and norepinephrine (NE) systems is disrupted in depressed patients. We obtained 6‐h concentration time series of tryptophan, 5‐HIAA, NE, and 3‐methoxy‐4‐hydroxyphenylglycol (MHPG) in the CSF of 10 patients with major depression and in 10 normal volunteers. No significant differences in CSF tryptophan, 5‐HIAA, NE, or MHPG concentrations or rhythms were observed between normal volunteers and depressed patients. Neither were there differences in the mean tryptophan‐to‐serotonin ratio. However, a negative linear relationship was observed between mean concentrations of 5‐HIAA and NE in the CSF of the normal volunteers (r = 0.916 [r2 = 0.839], df = 9, P < 0.001) while, in contrast, depressed patients showed no such relationship (r = +0.094 [r2 = 0.00877], df = 9, n.s.). Furthermore, the correlation coefficients expressing the relationship between CSF MHPG and CSF 5‐HIAA within the normal and depressed groups were significantly different. These data support the hypothesis that a disturbance in the interaction between the serotonergic and noradrenergic systems can exist in depressive illness in the absence of any simple 5HT or NE deficit or surplus. Depression and Anxiety 6:89–94, 1997.© 1997 Wiley‐Liss, Inc.

Cholecystokinin in human cerebrospinal fluid: concentrations, dynamics, molecular forms and relationship to fasting and feeding in health, depression and alcoholism

Very little is known about the physiologic significance of the gut-brain hormone cholecystokinin (CCK) in the human central nervous system, although the hormone has been hypothesized to be involved in the regulation of both appetite and anxiety. We continuously collected lumbar cerebrospinal fluid (CSF) via indwelling subarachnoid catheters in ten normal volunteers, ten patients with major depression and five abstinent alcoholic humans, while fasting and after eating. Five other healthy subjects were fasted throughout the experiment. We quantified CSF immunoreactive cholecystokinin (IR-CCK) and glucose concentrations at 10-min intervals from 11.00 to 17.00 h. No difference in CSF IR-CCK concentration, half-life or rhythm was observed between normal volunteers and either depressed or alcoholic patients. Fasting CSF IR-CCK concentrations were 1.3 +/- 0.18, 1.3 +/- 0.21 and 1.2 +/- 0.21 fmol/ml (mean +/- S.E.M.) in normal volunteers, depressed patients and alcoholic patients, respectively. After eating, CSF IR-CCK concentrations rose to 1.5 +/- 0.21, 1.5 +/- 0.24 and 1.4 +/- 0.26 fmol/ml, respectively. Normal volunteers who did not eat had similar basal CSF IR-CCK concentrations (1.1 +/- 0.1 fmol/ml) which similarly rose to 1.4 +/- 0.13 fmol/ml during the sampling interval. In contrast, CSF glucose concentrations rose only in the subjects who ate, beginning to rise after about 1 h and remaining elevated for at least 3 h after eating. These data suggest the existence of a diurnal rhythm of IR-CCK release into CSF, as opposed to a response to feeding. The disappearance half-time of CCK in human CSF is less than 13 min.(ABSTRACT TRUNCATED AT 250 WORDS)

Sleep deprivation accelerates the response to nortriptyline

1. The authors examined the effect of total sleep deprivation (SD) in combination with nortriptyline in 20 patients with major depressive disorder (MDD). Patients underwent a 36-hour SD procedure followed by nortriptyline started on the evening after SD, with ratings for two weeks. 2. Eleven (55%) patients were responders; they showed a rapid and sustained remission after SD, whereas non-responders demonstrated the delayed results expected with nortriptyline. 3. High initial depression scores and absence of depersonalization were associated with response to SD, while being female and middle insomnia were associated with response to the combined regimen. 4. The combination of SD with antidepressants proves to be an effective and safe treatment modality.