Adelio Lucca

Total sleep deprivation combined with lithium and light therapy in the treatment of bipolar depression: replication of main effects and interaction.

The clinical usefulness of total sleep deprivation (TSD) in the treatment of bipolar depression is hampered by a high-rate short-term relapse. Previous literature has suggested that both long-term lithium treatment and light therapy could successfully prevent relapse. We randomized 115 bipolar depressed inpatients to receive three cycles of TSD, alone or in combination with morning light exposure, given at an intensity of 150 or 2500 lux. Forty-nine patients were undergoing long-term treatment with lithium salts (at least 6 months), while 66 patients were taking no psychotropic medication. Mood was self-rated by the Visual Analogue Scale three times a day during treatment. The results showed that both light therapy and ongoing lithium treatment significantly enhanced the effects of TSD on the perceived mood, with no additional benefit when the two treatments were combined. Subjective sleepiness during TSD, as rated by the self-administered Stanford Sleepiness Scale, was significantly reduced by light exposure, and was correlated with the outcome. This study confirms the possibility of obtaining a sustained antidepressant response to TSD in bipolar patients.

Transcranial magnetic stimulation in treatment-resistant depressed patients: A double-blind, placebo-controlled trial

This 5-week, randomized, double-blind, placebo-controlled trial investigated the efficacy and tolerability of high frequency repetitive transcranial magnetic stimulation (rTMS) directed to the left prefrontal cortex in drug-resistant depressed patients. Fifty-four patients were randomly assigned to receive 10 daily applications of either real or sham rTMS. Subjects assigned to receive active stimulation were divided into two further subgroups according to the intensity of stimulation: 80% vs. 100% of motor threshold (MT). At study completion, the response rates were 61.1% (n=11), 27.8% (n=5) and 6.2% (n=1) for the 100% MT group, 80% MT group and sham group, respectively. A significant difference (Pearson chi(2) test) was found between the 100% MT and sham groups, while the 80% MT group did not differ significantly from the sham group. Between the two active groups, a marginally significant difference was observed. Analysis of variance with repeated measures on Hamilton Depression Rating Scale scores revealed a significantly different decrease over time of depressive symptomatology among the three treatment groups. Treatment response appeared to be unrelated to the demographic and clinical characteristics recorded, and on the whole the technique was well tolerated. The results of this double-blind trial showed that rTMS may be a useful and safe adjunctive treatment for drug-resistant depressed patients.

Sleep deprivation hastens the antidepressant action of fluoxetine.

Among ten bipolar depressed patients admitted to our psychiatric ward, five patients were treated with fluoxetine alone and five subjects were treated with fluoxetine in association with total sleep deprivation (TSD) in order to evaluate the effect of the interaction between the administration of the serotonergic antidepressant compound fluoxetine and repeated cycles of TSD. Patients treated with fluoxetine plus repeated TSD showed a faster amelioration of depressive symptomatology compared with the other group. We discuss our findings hypothesizing an enhancement in dopaminergic and possibly in serotonergic transmission due to repeated TSD adding to the increase in serotonergic transmission due to fluoxetine medication.

Amino acid patterns in schizophrenia: Some new findings

Blood concentrations of various amino acids were measured in schizophrenic patients and control subjects. Significantly higher blood concentrations of glycine, glutamate, and serine were found in the schizophrenic patients. Glycine was abnormally elevated in subjects with paranoid or undifferentiated schizophrenia, but not in disorganized patients. Since glutamate, glycine, and serine play a complex role in the regulation of N-methyl-D-aspartate (NMDA) receptors, which are important in the control of normal cognitive processes, we hypothesized that the elevated levels of these amino acids might disrupt the normal functioning of NMDA receptors and might be involved in the pathophysiology of schizophrenia.

Interleukine-6 serum levels correlate with response to antidepressant sleep deprivation and sleep phase advance

Unstimulated production of interleukine-6 (IL-6) is known to be enhanced in patients affected by a major depressive episode. Recent studies supported a role for basal IL-6 levels in predicting response to antidepressant drug treatments. In a sample of 10 consecutively admitted drug-free bipolar depressed inpatients, we investigated the possible correlation between unstimulated pretreatment production of IL-6 and antidepressant response to a night of total sleep deprivation (TSD) followed by a night of sleep phase advance (SPA), a nonpharmacologic treatment which is known to rapidly improve depressive symptomatology. Changes in perceived mood during treatment were recorded with self-administered Visual Analogue Scales (VAS). We observed a significant inverse correlation between IL-6 serum levels and VAS scores after treatment, meaning that higher IL-6 values before treatment were associated with worse response. This finding is in agreement with previous studies about amitriptyline and lithium antidepressant treatments. Our preliminary finding confirms the clinical value of IL-6 baseline concentration as a predictor of response to antidepressant treatment.

DECREASE IN PLASMA PHENYLALANINE AND TYROSINE AFTER PHENYLALANINE-TYROSINE FREE AMINO ACID SOLUTIONS IN MAN

After an overnight fast, 5 male healthy subjects ingested increasing amounts of a solution containing a fixed proportion of seven essential amino acids (L-isoleucine, 13.3%; L-leucine, 21.0%; L-lysine, 15.2%; L-methionine, 21.0%; L-threonine, 9.5%; L-tryptophan, 4.8% and L-valine, 15.2%) and lacking phenylalanine and tyrosine. The solutions caused a rapid fall in plasma phenylalanine and tyrosine which was proportional to the total amount of amino acids ingested. Following the highest dose administered (31.5 g) plasma phenylalanine and tyrosine fell to a minimum of, respectively, 12.7% and 29.8% the initial levels and remained markedly reduced at 6 hours after treatment. The decrease of tyrosine and phenylalanine levels was associated with a decrease of systolic and diastolic arterial pressure.

A Symptom-Specific Analysis of the Effect of High-Frequency Left or Low-Frequency Right Transcranial Magnetic Stimulation over the Dorsolateral Prefrontal Cortex in Major Depression

Background: We have investigated the efficacy of high-frequency left (HFL) versus low-frequency right (LFR) repetitive transcranial magnetic stimulation (rTMS) in depression, focusing on specific symptoms as possible predictors of outcome for these two different types of stimulation. Method: Seventy-four outpatients with a major depressive episode treated with an adequate antidepressant dosage for at least 4 weeks were included in our study and randomly assigned to two different groups: HFL or LFR rTMS. The Hamilton Rating Scale for Depression (HAM-D) items were pooled into 6 factors to evaluate specific symptoms as possible predictors of response. Results: Twenty-one out of 32 patients (65.6%) and 24 out of 42 patients (57.1%) were responders in the HFL and LFR groups, respectively. No significant difference in response rate was observed. Considering the whole sample, we found an inverse correlation between activity and HAM-D score reduction and a significant positive relation between somatic anxiety and outcome. An inverse correlation between psychic anxiety and HAM-D score reduction emerged considering the HFL group. In the LFR group, there was a significant negative relationship between baseline activity and the outcome. Conclusion: These findings support the hypothesis that LFR rTMS could be as effective as HFL rTMS and more suitable for patients with a higher anxiety degree, particularly in bipolar patients.

Effects of fluvoxamine treatment on the in vivo binding of [F-18]FESP in drug naive depressed patients: a PET study

This study investigates the effect of chronic treatment with Fluvoxamine, a potent and specific serotonin reuptake sites inhibitor (SSRI), on 5HT(2) serotonin and D(2) dopamine receptors in the brain of drug naive unipolar depressed patients. Drug effect was evaluated in different cortical areas and in the basal ganglia by positron emission tomography (PET) and fluoro-ethyl-spiperone ([(18)F]FESP), an high affinity 5HT(2) serotonin and D(2) dopamine receptors antagonist. Patients underwent a PET study at recruitment and after clinical response to Fluvoxamine treatment. Nine of the 15 patients recruited completed the study. Fluvoxamine treatment significantly improved clinical symptoms and modified [(18)F]FESP binding in the frontal and occipital cortex of all of the nine patients who completed the study; in these regions a mean 31% increase in the in vivo [(18)F]FESP binding was found (P < 0.01). On the contrary, no significant changes in the in vivo [(18)F]FESP binding were found in the basal ganglia where [(18)F]FESP binds mainly to D(2) dopamine receptors. Chronic treatment with Fluvoxamine significantly increases the in vivo binding of [(18)F]FESP in the frontal and occipital cortex of drug naive unipolar depressed patients. The increase of the in vivo binding of [(18)F]FESP may reflect a modification in 5HT(2) binding capacity secondary to changes in cortical serotonin activity.

Role of serotonergic gene polymorphisms on response to transcranial magnetic stimulation in depression

Transcranial magnetic stimulation (TMS) has been extensively studied as a treatment for Major Depression. However, no data are available about the role of genetic variables on the response to this treatment. We analysed the role of two polymorphisms that influence the response to antidepressants: the polymorphisms of the serotonin transporter promoter region (SERTPR) and of the 5-HT(1A) serotonergic receptor promoter region (-1019C/G). Ninety-nine patients from two double-blind, randomised, sham-controlled TMS trials were enrolled. There was a significant influence (p=0.016) of the SERTPR polymorphism on treatment outcome, without differences between active and sham stimulation. Conversely, there was a significant (p=0.014) interaction between 5-HT(1A) genotype and type of stimulation: C/C patients showed a higher difference between active and sham stimulation, indicating that these patients benefited more by TMS than C/G and G/G subjects. Our sample has not the power to control for the possible influence of different medications on these results.

Assessing the Effects of Electroconvulsive Therapy on Cortical Excitability by Means of Transcranial Magnetic Stimulation and Electroencephalography

Electroconvulsive therapy (ECT) has significant short-term antidepressant effects on drug-resistant patients with severe major depression. Animal studies have demonstrated that electroconvulsive seizures produce potentiation-like synaptic remodeling in both sub-cortical and frontal cortical circuits. However, the electrophysiological effects of ECT in the human brain are not known. In this work, we evaluated whether ECT induces a measurable change in the excitability of frontal cortical circuits in humans. Electroencephalographic (EEG) potentials evoked by transcranial magnetic stimulation (TMS) were collected before and after a course of ECT in eight patients with severe major depression. Cortical excitability was measured from the early and local EEG response to TMS. Clinical assessment confirmed the beneficial effects of ECT on depressive symptoms at the group level. TMS/EEG measurements revealed a clear-cut increase of frontal cortical excitability after ECT as compared to baseline, that was significant in each and every patient. The present findings corroborate in humans the idea that ECT may produce synaptic potentiation, as previously observed in animal studies. Moreover, results suggest that TMS/EEG may be employed in depressed patients to monitor longitudinally the electrophysiological effects of different therapeutic neuromodulators, e.g. ECT, repetitive TMS, and sleep deprivation. To the extent that depression involves an alteration of frontal cortical excitability, these measurements may be used to guide and evaluate treatment progression over time at the single-patient level.