Giulia Perini

The inflammatory & neurodegenerative (I&ND) hypothesis of depression: leads for future research and new drug developments in depression

Despite extensive research, the current theories on serotonergic dysfunctions and cortisol hypersecretion do not provide sufficient explanations for the nature of depression. Rational treatments aimed at causal factors of depression are not available yet. With the currently available antidepressant drugs, which mainly target serotonin, less than two thirds of depressed patients achieve remission. There is now evidence that inflammatory and neurodegenerative (I&ND) processes play an important role in depression and that enhanced neurodegeneration in depression may–at least partly–be caused by inflammatory processes. Multiple inflammatory-cytokines, oxygen radical damage, tryptophan catabolites–and neurodegenerative biomarkers have been established in patients with depression and these findings are corroborated by animal models of depression. A number of vulnerability factors may predispose towards depression by enhancing inflammatory reactions, e.g. lower peptidase activities (dipeptidyl-peptidase IV, DPP IV), lower omega-3 polyunsaturated levels and an increased gut permeability (leaky gut). The cytokine hypothesis considers that external, e.g. psychosocial stressors, and internal stressors, e.g. organic inflammatory disorders or conditions, such as the postpartum period, may trigger depression via inflammatory processes. Most if not all antidepressants have specific anti-inflammatory effects, while restoration of decreased neurogenesis, which may be induced by inflammatory processes, may be related to the therapeutic efficacy of antidepressant treatments. Future research to disentangle the complex etiology of depression calls for a powerful paradigm shift, i.e. by means of a high throughput-high quality screening, including functional genetics and genotyping microarrays; established and novel animal and ex vivo–in vitro models for depression, such as new transgenic mouse models and endophenotype-based animal models, specific cell lines, in vivo and ex vivo electroporation, and organotypic brain slice culture models. This screening will allow to: 1) discover new I&ND biomarkers, both at the level of gene expression and the phenotype; and elucidate the underlying molecular I&ND pathways causing depression; and 2) identify new therapeutic targets in the I&ND pathways; develop new anti-I&ND drugs for these targets; select existing anti-I&ND drugs or substances that could augment the efficacy of antidepressants; and predict therapeutic response by genetic I&ND profiles.

Italian Validation of the Symptom Rating Test (SRT) and Symptom Questionnaire (SQ)

Two self-rating scales of psychological distress, the Symptom Rating Test (SRT) and the Symptom Questionnaire (SQ), have been validated in translations in Italy. They were administered in several studies to psychiatric patients (neurotics and depressives), matched controls, and patients suffering from various organic illnesses (dermatologic disorders, hypertension, secondary amenorrhea and patients undergoing amniocentesis). The SRT and the SQ sensitively discriminated between psychiatric patients and normals, between different levels of psychological distress in several of the somatic illnesses, and detected significant changes in the psychological status of patients participating in medical procedures such as amniocentesis. The scales were found to be useful in research in psychiatry and psychosomatic medicine. The findings suggest that the Italian translations are valid and sensitive scales of distress and can apparently be used as effectively in research as the original. They are likely to be of value in cross-cultural research in Canada. Both scales may be helpful in the psychological assessment of Italian immigrants in North America and Australia, especially in those whose English is poor.

Depression and anxiety in complex partial seizures.

In order to evaluate the effect of lateralization of epileptogenic lesions on mood changes (depression-mania) and anxiety (state and trait), twenty patients with complex partial seizures and nineteen controls were assessed with depression scales (Beck, Columbia M-D) and the State and Trait Anxiety Inventory. Nine patients had left temporal foci, eight had right foci, as assessed by the side of seizure onset during closed-circuit television-EEG telemetry recording. Left patients scored significantly higher than both right and control groups on depression and trait anxiety. Our results are consistent with those of previous reports on patients with localized epileptogenic and nonepileptogenic lesions. Patients with left side involvement seem more prone to experience dysphoric changes and depressive symptoms than those with right involvement.

Plasma Interleukin-1β and Tumor Necrosis Factor Concentrations in Obsessive–Compulsive Disorders

Plasma interleukin-1 beta (Il-1 beta) and tumor necrosis factor-alpha (TNF-alpha) concentrations were measured twice, at a 48-hour interval, in 27 drug-free obsessive-compulsive patients (12 women and 15 men) and in 27 sex-age-matched healthy controls. Il-1 beta and TNF-alpha concentrations were significantly lower in patients than in controls, whereas there were no differences in either group between men and women, between the samples of the two days, or, in the patients, between those who had and those who had not been previously treated with psychopharmacologic drugs.

Rating depression in normals and depressives: Observer versus self-rating scales

Different methods of assessing depression and anxiety were tested in 20 patients suffering from a major depressive disorder with melancholia and 20 matched control subjects. Depressives were assessed before and after treatment with amitriptyline and normals were retested at the same interval. The scales used were: Paykels Clinical Interview for Depression--which is an expanded version of the Hamilton Depression Rating Scale; the Brief Depression Rating Scale; and Symptom Questionnaire (SQ). All scales discriminated sensitively between patients and normals and the scores changed substantially with treatment. Except for the well-being subscales of the SQ, the scales showed an adequate test-retest reliability in normals. Although all scales were suitable for the measurement of depression, they differed in psychometric properties. For example, the Depression subscale of the SQ showed an unusually high test-retest reliability in normals, whereas the Contentment subscale was unreliable. Yet, the latter has been found to be highly sensitive in detecting differences between the effects of psychotropic drugs and placebo in drug trials, so it appears to measure sensitively a fleeting mood. The combined use of all three scales in patients with affective disorders yields information that might not be revealed if only one scale is used.

Plasma concentrations of anxiolytic neuroactive steroids in men with panic disorder

Plasma concentrations of neuroactive steroids in men with panic disorder (PD) were measured to evaluate their relations to psychopathology both before and during treatment. Participants comprised 13 men with PD and 10 normal controls. Patients were evaluated while drug-free as well as after 1 and 2 months of paroxetine therapy. Psychopathology was assessed by the State-Trait Anxiety Inventory (STAI), the Panic-Associated Symptom Scale, and the Fear Questionnaire total score. Plasma concentrations of steroids were measured by radioimmunoassay. The plasma concentrations of progesterone and dehydroepiandrosterone were greater in drug-free patients than in controls, whereas those of allopregnanolone and tetrahydrodeoxycorticosterone did not differ between the two groups. Paroxetine treatment for 2 months significantly increased the plasma concentration of allopregnanolone but did not affect those of the other steroids. At 2 months of therapy, allopregnanolone concentrations in patients were significantly greater than those in controls. The plasma concentrations of progesterone and tetrahydrodeoxycorticosterone correlated with the STAI state score in patients before treatment. Our data suggest that neuroactive steroids may play a role in PD in men.

Imipramine in Alopecia areata

Alopecia areata (AA) is a dermatologic disease whose onset is significantly associated to life events. Its course may often be characterized by high levels of anxiety and depression. These observations suggested a rationale for using an antidepressant in AA. Thirteen patients were enrolled in a double-blind, placebo-controlled study of efficacy of imipramine in alopecia. After six months clinically significant hair regrowth occurred in 5 of the 7 patients on imipramine, whereas no response was observed in the placebo group. An improvement in psychic symptomatology was present in both groups. Our preliminary results indicate the potential efficacy of imipramine in patients with AA, not acting directly through a reduction of anxiety or depression.

Characterization of a 7% carbon dioxide (CO2) inhalation paradigm to evoke anxiety symptoms in healthy subjects

The present study is aimed at characterizing the carbon dioxide (CO2) procedure in healthy subjects to achieve reliable provocation of anxiety symptoms. Thirty healthy subjects inhaled in single-blind both compressed air and 7% CO2 mixture. Panic Symptom List (PSLIII-R), Visual Analogue Scale-Anxiety (VAS-A), State Anxiety Inventory (STAI-Y/1), respiratory parameters and skin conductance were measured. ‘Responders’ were classified depending on PSLIII-R scores after CO2. Twelve out of the 21 ‘responders’ performed a second test to assess test-retest repeatability. In 21 subjects%VAS-A (45.4 32.1) and PSLIII-R (pre-test 2.3 2.1, post-test 17.5 8.2) but not STAI-Y/1, significantly increased during CO2 inhalation. Respiratory Rate, Minute Volume, end-Tidal CO2 and skin conductance rose in ‘responders’. Repeatability was studied with Bland-Altman plots, revealing mean difference between tests close to 0 for both%VAS-A and PSLIII-R. Among physiologic parameters, end-Tidal CO2 and Respiratory Rate showed good repeatability, with a within-subject CV of 9.2% and 6%, respectively. The challenge produced measurable response in healthy subjects. Good test-retest repeatability was observed in ‘responders’. These data indicate that the test can be suitable for testing putative anti-panic or anxiolytic drugs in clinical studies using a within subject, crossover design.

Hostility and recovery from melancholia.

Twenty inpatients suffering from major depressive illness with melancholia were administered the hostility subscale of the Kellner Symptom Questionnaire and Paykels Clinical Interview for Depression before and after treatment with amitriptyline. A matched control group of normal subjects had the same assessments at two points in time. Hostility decreased and friendliness increased in depressives after amitriptyline; upon recovery, there were no significant differences in hostility between depressed patients and control subjects, whereas such differences were striking during the illness. Patients who had reported losses before onset of illness rated themselves as more friendly than the other depressives; their hostility did not significantly decrease with recovery. The results suggest that hostility improves with the treatment of depression; life events appear to influence the degree of hostility in depressive illness as well as the response to treatment.

Intellectual impairment and cognitive evoked potentials in myotonic dystrophy

Twenty-seven patients with myotonic dystrophy (MD) and 20 control subjects were tested using neuropsychological and electrophysiological measures. MD patients reported significantly lower scores on the Wechsler Adult Intelligence Scale and the Mini-Mental State Examination. P3 amplitude of auditory event-related potentials was significantly reduced in 14 patients. P3 latency was normal. In 13 patients, P3 was not elicited. Our results clearly show the presence of a significant impairment of cognitive functioning, as assessed by psychometric measures, in more than 50% of MD patients. Discriminant function correctly classified 92% of patients, using event-related potentials and neuropsychological variables.