Massimo Pasquini

Immunotherapy with interferon-alpha in patients affected by chronic hepatitis C induces an intercorrelated stimulation of the cytokine network and an increase in depressive and anxiety symptoms.

Immunotherapy with interferon-alpha (IFNalpha) may induce depressive symptoms, anxiety and major depression when administered for at least 1-3 months at a dose of 3-10 MUI daily, twice or three times a week. Previously, it has been shown that immunotherapy with interleukin-2 (IL-2) significantly induces the cytokine network, as measured by increases in serum IL-6, IL-10 and the IL-2 receptor (IL-2R), and that the immunotherapy-induced changes in the cytokine network are significantly correlated with the increases in depression ratings. The main aim of this study was to examine the effects of immunotherapy with IFNalpha on the cytokine network in relation to changes in depression and anxiety ratings. Fourteen patients, affected by chronic active C-hepatitis, were treated with IFNalpha (3-6 MUI s.c. three/six times a week for 6 months) and had measurements of serum IFN-gamma (IFNgamma), IL-2, IL-6, IL-6R, IL-8 and IL-10 before starting therapy and 2, 4, 16 and 24 weeks after immunotherapy with IFNalpha. Severity of depression and anxiety were measured with the Montgomery-Asberg Depression Rating Scale (MADRS) and the Hamilton Anxiety Rating Scale (HAM-A), respectively. Repeated measure (RM) design ANOVAs showed significantly higher MADRS and HAM-A scores 2-4 weeks and 4-6 months after starting IFNalpha-based immunotherapy than at baseline. RM design ANOVAs showed significantly higher serum IL-6 and IL-8 levels 2-4 weeks after starting IFNalpha-based immunotherapy and higher serum IL-10 levels 2-4 weeks and 4-6 months after starting therapy than at baseline. There were significant relationships between the IFNalpha-induced changes in serum IL-6 or IL-8 and the depression and anxiety scores. The findings show that IFNalpha-based immunotherapy induces the cytokine network and that IFNalpha-induced increases in IL-6 predicts the development of depressive symptoms. Depressive symptoms following IFNalpha treatment may be secondary to cytokine induction, including that of IL-6.

Depression in cancer patients: a critical review

Cancer patients experience several stressors and emotional upheavals. Fear of death, interruption of life plans, changes in body image and self-esteem, changes in social role and lifestyle are all important issues to be faced. Moreover, Depressive Disorders may impact the course of the disease and compliance. The cost and prevalence, the impairment caused, and the diagnostic and therapeutic uncertainty surrounding depressive symptoms among cancer patients make these conditions a priority for research. In this article we discuss recent data, focusing on detection of Depressive Disorders, biological correlates, treatments and unmet needs of depressed cancer patients.

Treatment with interferon-alpha (IFNα) of hepatitis C patients induces lower serum dipeptidyl peptidase IV activity, which is related to IFNα-induced depressive and anxiety symptoms and immune activation

We have shown that treatment with interleukin-2 (IL-2) or interferon-α (IFNα) may induce depressive symptoms and activation of the cytokine network and that IL-2 treatment may diminish serum dipeptidyl pepdidase IV (DPP IV) activity.1–3 DPP IV (EC 3.4.14.5) is a membrane bound serine protease which catalyzes the cleavage of some cytokines and neuroactive peptides which modulate T cell activity.4 The aims of the present study were to examine the effects of IFNα-based immunotherapy on serum DPP IV activity in relation to induction of the inflammatory response system. In 18 patients with chronic active hepatitis C, we determined the Montgomery and Asberg Rating Scale (MADRS),5 the Hamilton Anxiety Rating Scale (HAM-A),6 serum DPP IV activity, the kynurenine/tryptophan (K/T) quotient, which is an indicator of cytokine (in particular IFN)-induced catabolism of tryptophan,7 and serum interleukin-8 (IL-8) before starting therapy and 2, 4, 16 and 24 weeks after immunotherapy with IFNα. IFNα-immunotherapy significantly suppressed serum DPP IV 2–4 weeks and 16–24 weeks after starting IFNα-based immunotherapy. The reduction in serum DPP IV activity was more pronounced 16–24 weeks after starting immunotherapy than after 2–4 weeks. The IFNα-induced suppression of serum DPP IV activity was significantly correlated to IFNα-induced increases in the MADRS and HAM-A and increases in the K/T quotient and serum IL-8. In conclusion, long-term immunotherapy with IFNα suppresses serum DPP IV activity and the immunotherapy-induced changes in DPP IV are related to increases in severity of depression, anxiety and activation of the inflammatory response system.

Psychiatric disorders in adult-onset focal dystonia: A case-control study†

In a single‐center, case–control study, we investigated the frequency and types of psychiatric disturbances in 89 consecutive patients with various primary focal dystonias (34 had cervical dystonia (CD), 28 blepharospasm (BPS), 16 laryngeal dystonia (LD), and 11 arm dystonia), 62 healthy control subjects and as controls for BPS, 26 patients with hemifacial spasm (HFS). Patients and controls underwent a full psychiatric evaluation. Diagnosis was based on the structured clinical interview for DSM‐IV, obsessive‐compulsive disorder (OCD) was assessed with the Yale‐Brown Obsessive‐Compulsive scale, anxiety with the Hamilton Rating Scale for Anxiety, the severity of depression with the Beck Depression Inventory. Of the 89 patients with focal dystonias studied, 51 patients (57.3%) had a diagnosis of psychiatric disorders compared with only 15 of 62 healthy subjects (24.1%) and 9 of the patients with HFS (34.6%). Depressive disorders were more frequent in the CD and BPS groups than in healthy controls, whereas the frequency of anxiety disorders, OCDs or adjustment disorders approached that of healthy subjects. No difference was found in the frequency of any specific psychiatric disorder in patients with LD and arm dystonia and healthy controls. In 35 of 51 patients who had psychiatric disorders, these started before and in 16 patients after the onset of dystonia. No differences were found in age, dystonia severity, and duration of botulinum toxin treatment between patients with and without psychiatric disturbances. The most common psychiatric features in patients with CD and BPS are depressive disorders.

Memantine augmentation for refractory obsessive-compulsive disorder.

Glutamatergic hyperactivity hypothesis in obsessive-compulsive disorder (OCD) has been proposed but not tested. Memantine is an uncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist. We report two cases of refractory obsessive-compulsive disorder treated with an augmentation of memantine at 15 mg/day. The first case did not benefit from such treatment, while the second showed immediate and substantial improvement. Contrasting results, reflecting different subtypes of OCD, are discussed. We hypothesized that in certain OCD subtypes an agent that enhances memory for actions may promote a reduction in orbitofrontal activation.

Relevance of Anger and Irritability in Outpatients with Major Depressive Disorder

Introduction: Current psychiatric classification systems underestimate the part played by anger and aggressiveness in unipolar depression. This study was designed to assess the relevance of anger, irritability, aggressiveness, hostility, and psychomotor activation in major depressive disorder. Methods: A total of 222 newly admitted consecutive outpatients with major depressive disorder (mean age 48.9 years, 64.4% females) were enrolled in the study. They had no comorbid axis I or II DSM-IV disorder, and they received no treatment with antidepressants in the preceding 2 months. They were assessed with the SVARAD, a validated scale for the rapid assessment of the main psychopathological dimensions. Principal component analysis was performed on SVARAD items. Results: We obtained a three-factor solution accounting for 47.4% of total variance. The factors were interpreted as ‘anger/irritability’, ‘depression’, and ‘anxiety’, respectively. The anger/irritability dimension was clinically relevant in 23% of patients. Anger/aggressiveness was especially frequent (21.6%), whereas psychomotor activation was infrequent (0.9%). Discussion: In depressive disorders, there are psychopathological dimensions other than depressed mood and anxiety that deserve greater clinical recognition and research. Our study suggests that one of these symptom clusters includes anger, irritability, aggressiveness, and hostility. The relevance of this dimension was not related to concurrent pharmacological treatment. Misdiagnosis of bipolar II disorder is also unlikely to explain our findings. Possibly, personality factors might at least partly explain the occurrence of anger and aggressiveness in several depressed patients. Attachment theory suggests that anger might also be conceived as part of the protest-despair-detachment reaction to a loss, either actual or symbolic.

Psychopathological dimensions of depression: a factor study of the 17-item Hamilton depression rating scale in unipolar depressed outpatients.

BACKGROUND Agreement on the factor structure of the Hamilton Depression Rating Scale (HDRS) has not been consistent among studies, and some investigators argued that the scales factor structure is not reliable. This study aimed at shedding more light on this debated issue. METHODS We studied 186 adults with unipolar depression (Major Depressive Disorder, n=80; Dysthymic Disorder, n=71; Depressive Disorder Not Otherwise Specified, n=25; Adjustment Disorder, n=10). They had no comorbid DSM-IV axis I or axis II disorders, and had received no treatment with antidepressant drugs in the previous 2 months. The factor structure of the scale was studied using the principal factor method, followed by oblique rotation. Factor scores were computed for each subject using the regression method. RESULTS Using the scree-test criterion for factor extraction, we obtained a four-factor solution, explaining 43.8% of total variance. The four factors extracted were identified as (1) somatic anxiety/somatization factor; (2) a psychic anxiety dimension; (3) a pure depressive dimension; and (4) anorexia factor. Patients with Major Depressive Disorder scored significantly higher than patients with other diagnoses on the pure depressive dimension. LIMITATIONS These results need to be replicated in different cultures, using analogous factoring techniques. CONCLUSIONS Though not exhibiting factorial invariance in the stricter sense of the term, the 17-item HDRS did exhibit a relatively reliable factor structure. Our analysis provides further evidence that the scale is multidimensional. However, as long as the multidimensional character of the scale is taken into account the scale should be able to play a useful role in clinical research.

Abnormal cortical and brain stem plasticity in Gilles de la Tourette syndrome

We investigated primary motor cortex and brain stem plasticity in patients with Gilles de la Tourette syndrome. The study group comprised 12 patients with Gilles de la Tourette syndrome and 24 healthy subjects. Patients were clinically evaluated using the Yale Global Tic Severity Scale. We tested cortical plasticity by conditioning left primary motor cortex with intermittent or continuous theta‐burst stimulation in 2 separate sessions. Test stimulation consisted of 20 motor‐evoked potentials recorded from right first interosseous muscle before and after theta‐burst stimulation. We also tested brain stem plasticity by conditioning the right supraorbital nerve with facilitatory electric high‐frequency stimulation delivered at the same time as the late response of the blink reflex or inhibitory high‐frequency stimulation delivered before the late response on 2 separate sessions. Test stimulation consisted of 10 blink reflexes from the right orbicularis oculi muscle before and after high‐frequency stimulation. After intermittent theta‐burst stimulation, motor‐evoked potential amplitudes in healthy subjects increased significantly but remained unchanged in patients. Similarly, after continuous theta‐burst stimulation, motor‐evoked potential amplitudes decreased significantly in healthy subjects but did not in patients. After facilitatory high‐frequency stimulation, the blink reflex late response area in healthy subjects increased, whereas after inhibitory high‐frequency stimulation, it decreased. Conversely, in patients, both interventions left the blink reflex late response area unchanged. The lack of the expected inhibitory and facilitatory changes in motor‐evoked potential amplitudes and blink reflex late response area suggests that abnormal plasticity in the primary motor cortex and brain stem play a role in the pathophysiology of Gilles de la Tourette syndrome.

A large Italian family with Gilles de la Tourette syndrome: clinical study and analysis of the SLITRK1 gene.

Our objective was to report the clinical characteristics and to investigate the role of SLITRK1 gene in a large Italian family with Tourette syndrome (TS). The diagnosis of TS and chronic motor tics (CMT) was made according to “The Tourette Syndrome Classification Study Group” (1993). Psychiatric diagnoses were made by administering the Structured Clinical Interview for DSM and the Yale‐Brown Obsessive Compulsive Scale. Genetic study included direct sequencing and copy number analysis of the SLITRK1 gene, and haplotype analysis. We found tics or other behavioral manifestations in 15 subjects. Of these, 5 received a diagnosis of definite TS, 5 were classified as having definite CMT, 2 had definite nonspecific tic disorder, and 3 patients had obsessive–compulsive disorder without motor or phonic tics. Tics mainly involved the craniocervical district. Many patients with tics had coexisting psychiatric disorders, especially obsessive–compulsive disorder, performed poorly at school and had social problems. Direct sequencing and copy number analysis of the SLITRK1 gene, and haplotype analysis suggested that the SLITRK1 locus was not involved in this family. In conclusion, the distinctive clinical features in this family are the motor tics mainly involving the face and the neck and the severe coexisting psychiatric disorders. The negative results of the SLITRK1 analysis point to genetic heterogeneity in TS.

Non-motor symptoms in patients with adult-onset focal dystonia: Sensory and psychiatric disturbances *

Dystonia is characterized by the presence of involuntary muscle contractions that cause abnormal movements and posture. Adult onset focal dystonia include cervical dystonia, blepharospasm, arm dystonia and laryngeal dystonia. Besides motor manifestations, patients with focal dystonia frequently also display non-motor signs and symptoms. In this paper, we review the evidence of sensory and psychiatric disturbances in adult patients with focal dystonia. Clinical studies and neurophysiological investigations consistently show that the sensory system is involved in dystonia. Several studies have also demonstrated that neuropsychiatric disorders, particularly depression and anxiety, are more frequent in patients with focal dystonia, whereas data on obsessive compulsive disorders are more contrasting.