Low-frequency rTMS over right dorsolateral prefrontal cortex in the treatment of resistant depression: cognitive improvement is independent from clinical response, resting motor threshold is related to clinical response.

BACKGROUND: Clinical studies have shown that repetitive transcranial magnetic stimulation (rTMS) is effective in a certain percentage of treatment-resistant depression (TRD). The left dorsolateral prefrontal cortex (DLPFC) 10 Hz rTMS stimulation received FDA approval in 2008, although different rTMS protocols have also shown their effectiveness in reducing depressive symptoms. We investigated the clinical, cognitive and neurophysiologic effects of a 3 weeks' protocol of low-frequency rTMS applied over the right DLPFC in resistant depression. METHODS: Twenty-eight patients with TRD (age range 28-55) received low-frequency rTMS (1 Hz) over the right DLPFC in a 3-week open trial. Hamilton scales for depression and anxiety, Corsi block-tapping test, phonemic verbal fluency, right and left resting motor thresholds were evaluated in each subject over the trial period. RESULTS: At the end of the trial 42.9% of the subjects were considered as responders. A significant reduction of both HAMD (p < 0.001) and HAMA (p < 0.01) total scores was observed. At the 3rd week, the performances in Corsi test (p < 0.02) and phonemic verbal fluency (p = 0.065) were improved independently from depressive symptoms variation. At the end of the rTMS protocol, a significantly decreased left hemisphere resting motor threshold was registered (p < 0.01), while right hemisphere resting motor threshold did not show significant variation. CONCLUSION: Low-frequency rTMS over the right DLPFC appeared effective in 42.9% of depressive resistant subjects in this sample. A significant decrease in left hemisphere resting motor threshold was observed only in responders, while a trend for improvement in cognitive function has been found and appeared independent from clinical response.

Unilateral low frequency versus sequential bilateral repetitive transcranial magnetic stimulation: is simpler better for treatment of resistant depression?

Repetitive transcranial magnetic stimulation (rTMS) efficacy in the treatment of major depression has been shown in both low frequency right-sided and high frequency left-sided stimulation over the dorsolateral prefrontal cortex (DLPFC). The aim of the present investigation was to evaluate the hypothesis of an additive effect of bilateral stimulation compare to sequential to unilateral stimulation. Sixty patients with treatment-resistant depression were assigned to receive either low-frequency rTMS over the right DLPFC (140 s x 1 Hz) followed by controlateral sham (unilateral group, n=20), low frequency right DLPFC rTMS followed by left DLPFC high frequency rTMS (5 s x 10 Hz) (bilateral group, n=20), or bilateral sham (sham group, n=20) in a 3 weeks double-blind, randomized trial. The primary outcome variable was the score on Hamilton Depression Scale (HAM-D). Low frequency right-sided and sequential bilateral stimulation showed different antidepressant efficacy at 3 weeks and across the full duration of the study, only the unilateral method appearing significantly more effective than sham at the end of the trial, and correlated to the higher percent of remitters (30% of the group vs. 10% -bilateral- and 5% -sham). Unilateral stimulation, but not bilateral, showed higher antidepressant efficacy compared to sham stimulation. The data suggest that right-sided low frequency stimulation may be a first line treatment alternative in resistant depression. To confirm and extend these findings further studies require a longer follow-up period, supported by biological observation and replication.

Sumatriptan, 5-HT(1D) receptors and obsessive-compulsive disorder.

BACKGROUND: After considering the effects of 5-HT receptor agonists with different binding profiles on the symptoms of obsessive-compulsive disorder (OCD), Zohar and Kindler hypothesized that the 5-HT(1D) receptor was implicated in this disorder's pathophysiology. METHODS: We explored the 5-HT(1D) hypothesis in a 5-day, random, double-blind, placebo-controlled trial of oral sumatriptan 100 mg/day in medication-free adults with OCD. We hypothesized that sumatriptan, a 5-HT(1D) agonist, would diminish 5-HT release, thereby worsening OCD symptoms. We further hypothesized that by beginning to desensitize 5-HT(1D) receptors, sumatriptan pretreatment would promote a faster response or an increased likelihood of response to subsequent treatment with a selective serotonin reuptake inhibitor. RESULTS: The five sumatriptan subjects' OCD symptom worsening, as measured by the Yale-Brown scale ( upward arrow 17.6% (S.D. 14.6)), was significant when compared to the slight symptom decrease in the five placebo subjects ( downward arrow 5.2% (S.D. 4.9), P<0.015). The sumatriptan group did not exhibit a faster response or greater likelihood of response to a 90-day, open label trial of paroxetine. CONCLUSIONS: Longer term studies of the effects of 5-HT(1D) agonists on OCD symptoms are indicated. Zolmitriptan, a potent 5-HT(1D) receptor agonist with better penetration of the blood-brain barrier, may be a preferred challenge agent.

Social anxiety and premorbid personality disorders in paranoid schizophrenic patients treated with clozapine.

The concept of anxiety as a distinct comorbid disorder in schizophrenia has recently been rediscovered after having been neglected for a long period of time due to both theoretical and clinical approaches adopted from the appearance of the first edition of the Diagnostic and Statistical Manual of Mental Disorders in 1950. This rediscovery was accentuated by the fact that the concept of comorbidity in various psychiatric disorders has recently won widespread favor within the scientific community, and that the use of atypical neuroleptic medication to treat patients with schizophrenia has been reported to lead to the emergence of anxiety symptoms. Of the atypical neuroleptic medications used to treat schizophrenia, clozapine has most frequently been reported to induce anxiety symptoms. In this paper, 12 cases of patients with paranoid schizophrenia who developed social phobia during clozapine treatment are reported, and their response to fluoxetine augmentation is assessed. Premorbid personality disorders were also investigated; patients were assessed using the Structured Clinical Interview for DSM-III-R-Patient Version and the Structured Clinical Interview for DSM-IV Axis II Personality Disorders (DSM-III-R=Diagnostic and Statistical Manual of Mental Disorders, Third Edition Revised; DSM-IV=Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition). In addition, the Scale for the Assessment of Negative Symptoms, the Scale for the Assessment of Positive Symptoms, the Liebowitz Social Anxiety Scale (LSAS), the Frankfurt Beschwerde Fragebogen (Frankfurt Questionnaire of Complaints), and the Brief Psychiatric Rating Scale were used to rate clinical symptomatology. All patients were reevaluated after 12 weeks of cotreatment with clozapine and fluoxetine. In 8 (66.6%) of the 12 cases, symptoms responded (>/=35% LSAS score reduction) to an adjunctive regimen of fluoxetine. Furthermore, in 7 (58.3%) of the 12 cases, an anxious personality disorder (avoidant=33.3%; dependent=25%) was identified, but no significant differences in the prevalence of comorbid personality disorders emerged in comparison with a group of 16 patients with paranoid schizophrenia treated with clozapine who did not show symptoms of social phobia. The clinical relevance of the assessment and treatment of anxiety disorders is discussed in light of a clinical therapeutic approach that overcomes the implicit hierarchy of classification. Considering that the onset of anxiety-spectrum disorders (such as social phobia) can occur during the remission of psychotic symptoms in clozapine-treated patients with schizophrenia, a comprehensive approach to pharmacological therapy for patients with schizophrenia (or, at least for those treated with clozapine) should be adopted.

Shame and psychopathology.

The origins of the word "shame" recall the concept of the infraction of integrity both as scandal and as individualization. The human experience of shame stretches along a continuum from modesty to disabling interpersonal terror. Unlike other basic affects, its emergence is a fundamental moment in the process of self-awareness and self-object differentiation. Neglected by psychiatry because it was regarded as a moral concept, today it is possible to hypothesize that it has a biologic basis that one can attempt to describe in terms of corticothalamic pathways. In this respect, like other affects, it could be considered as a cognitive shortcut to activate specific and evolutionally useful behavioral patterns, such as concealment or a request for affiliation. It is fairly ubiquitous in psychopathology, but is clinically much more structured in its abnormal expressions in anxiety disorders, particularly social phobia, obsessive-compulsive disorder, eating disorders, body dysmorphic disorder, and even in bipolar mood disorder. In schizophrenia it has been described as being one stage in the construction of delusion. Its presence is connected to interpersonal relationship (altruism) though it seems absent in autism. The assessment of shame experiences in psychiatric patients could be useful for both pharmacological and psychotherapeutic strategies, and could provide a categorization of a new psychopathology based on abnormal affects.

Citalopram for treatment-resistant obsessive-compulsive disorder.

We investigated the comparative efficacy of citalopram vs. citalopram administered with clomipramine, in treatment-resistant obsessive-compulsive disorder (OCD). Sixteen adult outpatients participated in a 90-day, randomized, open-label trial. Eligible patients were aged 18 to 45 years, had moderate to severe DSM-III-R OCD of >/= one year's duration, a baseline Yale-Brown scale (Y-BOCS) score of >/= 25 and no other active axis I diagnosis, and had failed adequate clomipramine and fluoxetine trials. The citalopram-plus-clomipramine group (n = 9) experienced a significantly larger percent decrease in mean Y-BOCS score by day 90 than the citalopram alone group (n = 7). Only one citalopram patient decreased her score by >/= 35%, and two by >/= 25%. All nine citalopram-plus-clomipramine patients experienced decreases of 35%. Side effects were mild to moderate in both groups. We also treated with citalopram six OCD patients who had not tolerated fluoxetine alone and clomipramine alone; three achieved Y-BOCS score decreases of >/= 35% at 90 days. Since citalopram does not significantly affect clomipramine metabolism, the improvement in the combined drug group is unlikely to have resulted from increased plasma clomipramine levels. Double-blind controlled trials are needed of citalopram in OCD, and of combining citalopram with clomipramine in treatment-resistant OCD.

Basic symptoms and P300 abnormalities in young schizophrenic patients.

Among the reasons for the relatively limited number of investigations of self-knowledge phenomena should be included, in addition to theoretical motives, the difficulties regarding the use of instruments available for this kind of approach and their content validity. This study investigates the relationship between subjective and objective deficits in schizophrenia, taking into account subjective experiences of cognitive impairment, clinical symptoms, and cognitive evoked potentials (P300 component). A group of 36 young schizophrenic patients (29 on neuroleptic treatment and seven drug-naive) were considered, together with a comparison group of 36 healthy subjects. Auditory event-correlated potentials (ERPs) were obtained using a simple "oddball" paradigm. Clinical symptoms were rated with the Brief Psychiatric Rating Scale (BPRS) and Scales for the Assessment of Positive and Negative Symptoms (SAPS and SANS), and while subjective disturbances were assessed by the Frankfurter Beschwerde Fragebogen (FBF, also called the Complaint Questionnaire). Correlation analysis showed that P300 amplitude was inversely correlated with subjective experiences of cognitive deficit, especially in the area of automatic skills and overstimulation. No relationship emerged between BPRS, SANS, and SAPS scores and P300 alterations. The results suggest that subjective cognitive disturbances, more than objective symptoms, are related to P300 alterations in schizophrenia, and that the FBF questionnaire appropriately covers the domain of schizophrenic cognitive disorders.

Effects of clozapine on awareness of illness and cognition in schizophrenia.

Awareness of illness is a crucial factor in schizophrenia, both for clinical management and psychopathological modeling. To date, there has been relatively little investigation of the influence of treatment with conventional versus atypical neuroleptics in relation to awareness and cognitive functions. The effect of clozapine treatment, compared with conventional neuroleptics, was studied in 22 schizophrenic patients in a crossover study. The P300 component of the event-related potential and scores on the Scale for Unawareness of Mental Disorder (SUMD), the Extrapyramidal Side Effects Scale (EPS), and Andreasen's Scales for the Assessment of Positive (SAPS) and Negative Symptoms (SANS) were studied at time 1 (conventional neuroleptic treatment) and time 2 (after 6 months of treatment with clozapine, in patients who interrupted the previous conventional regimen). Significantly increased P300 amplitudes were associated with clozapine treatment, together with heightened insight and reduced involuntary movements. The results confirm the effectiveness of clozapine not only in enhancing neurocognitive function, but also in increasing awareness of illness in schizophrenic patients.

Awareness of illness and subjective experience of cognitive complaints in patients with bipolar I and bipolar II disorder.

OBJECTIVE: The authors' goal was to investigate the awareness of illness and subjective cognitive complaints of patients with either bipolar I disorder or bipolar II disorder during a phase of clinical stabilization. METHOD: They used a structured clinical interview, the Frankfurt Complaints Questionnaire, to determine subjective cognitive complaints, and the Scale of Unawareness of Mental Disorder to assess 57 consecutively enrolled patients with bipolar I or bipolar II disorder. RESULTS: Patients with bipolar II disorder had significantly less insight and a higher level of subjective complaints of stimulus overload than patients with bipolar I disorder. CONCLUSIONS: These results suggest that a severe deficit in self-awareness may constitute a distinguishing psychopathological characteristic of patients with bipolar II disorder. Further studies are required to determine if there are associated neuropsychological dysfunctions.

The emergence of social phobia during clozapine treatment and its response to fluoxetine augmentation.

BACKGROUND: The underlying neurochemical basis of social phobia has yet to be fully explained, but there are suggestions of serotonergic and dopaminergic dysfunction. The atypical neuroleptic clozapine has been reported to induce anxiety symptoms, probably owing to its effect on serotonergic pathways. We report 12 cases of schizophrenic patients who developed social phobia during clozapine treatment. METHOD: Patients were assessed using the Structured Clinical Interview for DSM-III-R, Patient Version, Scale for the Assessment of Negative Symptoms, Scale for the Assessment of Positive Symptoms, the Liebowitz Social Phobia Scale, and the Brief Psychiatric Rating Scale. They were reevaluated after 12 weeks of cotreatment with clozapine and fluoxetine. RESULTS: In 8 of the 12 cases, symptoms responded (> or = 35% reduction in Liebowitz Social Phobia Scale score) with an adjunctive regimen of fluoxetine. CONCLUSION: Data are discussed in light of neurochemical mechanisms and cognitive adaptations that could explain the onset of anxiety spectrum disorders (such as social phobia) in clozapine-treated schizophrenic subjects during remission of psychotic symptoms.

Pulse loading versus gradual dosing of intravenous clomipramine in obsessive-compulsive disorder.

OBJECTIVE: We compared gradually increased to pulse loaded doses of open-label, intravenous clomipramine (CMI) in patients with obsessive-compulsive disorder (OCD). METHOD: We treated adult outpatients with DSM-III-R OCD, who had no prior exposure to effective treatments. Pulse loading patients received 150 mg on day 1; 150 mg or 200 mg on day 2. Gradual dosing patients received 25 mg per day increased to 200 mg per day over 2 weeks and then continued for a mean of 43 days (n=40). After i.v. dosing, all patients received oral CMI; the total treatment period was 6 months. RESULTS: Pulse loading completers (n=7) had a rapid, dramatic response (mean Y-BOCS score decrease of 32% five days after pulse-loading). At this point (day 7), completers in the gradual intravenous group (n=20) exhibited no mean change in Y-BOCS score. The pulse loading group reached both a 25% or greater and a 50% or greater decrease in Y-BOCS score statistically and clinically significantly faster than the gradual group. CONCLUSIONS: Pulse-loaded intravenous CMI for the treatment of OCD deserves further study.

Eye movement abnormalities in anorexia nervosa.

The aim of the present study is to investigate smooth pursuit eye movement and saccadic performance in anorexia nervosa during a restored weight period and to determine if functional links can be made between eye movement performance and clinical features. SPEM parameters were recorded for 28 female anorectic out-patients (DSM IV), who had a body weight loss of up to 20% of ideal body weight. Twenty-eight comparison subjects were also tested. Clinically, each patient was assessed using the Eating Disorder Inventory (EDI), the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), the Structured Interview for Personality Disorders (SCID II), the Symptom Checklist-90-Revised (SCL-90-R) and the Hamilton Scale for Depression (HRSD). The anorectic patients performed slightly worse than the comparison subjects on a number of SPEM measures. No relationship was found between SPEM impairment and a global severity index of psychopathology (SCL 90-R GSI) or depressive symptoms. Moreover, OCD symptoms and scores on some EDI scales (such as perfectionism) appear related to the severity of the eye movement alterations. The evidence of SPEM abnormalities in a subgroup of anorectic patients during the remitted state and the relationship of the abnormalities to obsessive-compulsive symptoms are discussed. Results are in agreement with the hypothesis regarding the persistence of neurophysiological as well as psychopathological traits of disorder in anorectic patients.

Relapse in young paranoid schizophrenic patients: a prospective study of stressful life events, P300 measures, and coping.

OBJECTIVE: The authors investigated the relationship of cognitive and coping characteristics to stressful life events at the time of relapse in patients with recent-onset paranoid schizophrenia. METHOD: Over 6 years, the authors collected data on 41 schizophrenic outpatients aged 18-28 years at recruitment. The patients were rated prospectively every 2 weeks with the Brief Psychiatric Rating Scale, Scale for the Assessment of Negative Symptoms, Scale for the Assessment of Positive Symptoms, Global Assessment of Functioning Scale, and life events measures. The Frankfurt Questionnaire of Complaints was used to analyze subjective complaints regarding cognitive and coping abilities. The P300 auditory event-related potential was measured at recruitment to provide an index of information-processing capability. RESULTS: Patients without severe life events during the 1 month before relapse had a smaller P300, more subjective complaints, and less coping capacity than did relapsed schizophrenic subjects who had severe life events in the month before relapse. CONCLUSIONS: Relapses in subjects without severe life events were associated with fewer cognitive resources and less coping ability. Patients with normal P300 and adequate coping resources seemed to be able to deal better with stressful life events.

Citalopram in anorexia nervosa.

Thirthy-two female patients who had been diagnosed as having anorexia nervosa restricting subtype according to the DSM IV (Diagnostic and Statistical Manual of Mental Disorders-IV), were enrolled in a 6-month open trial with citalopram at a starting dose of 20 mg. At the end of the trial, 46.9% of the patients showed a satisfactory response, 34.4% an unsatisfactory response, improvement criteria being weight improvement, menstruation and score reduction on the Symptoms Checklist 90R. Anorectics also showed significant improvement in several Eating Disorder Inventory-2 (EDI-2) scores at the end of the trial, with greater improvement related to satisfactory response to citalopram. Data suggest that SSRI (Selective Serotonin Reuptake Inhibitor) Citalopram could be effective at least in a subgroup of anorectic patients, both on clinically objective and on subjective aspects of anorexia nervosa.

Smooth-pursuit eye movement and saccadic intrusions in obsessive-compulsive disorder.

Although several reports agree that smooth-pursuit eye movement (SPEM) is abnormal in some obsessive-compulsive disordered (OCD) patients, differences between treatments and lack of accuracy in control selection make the results controversial. Although reduced gain seems the most accepted abnormality, the characteristics of saccadic disruption of smooth pursuit are as yet unspecified. SPEMs in 21 OCD patients (DSM-III-R) and 21 healthy subjects recruited from the community were studied through a multiple target velocity task . The two groups were individually matched on age, gender, and level of education. None of the subjects had a history of substance dependence apart from the smokers who refrained from smoking in the 2 hours prior to the test. A significantly lower SPEM gain and increased number and frequency of anticipatory saccades (ASs) was found in OCD patients as compared with control subjects. No relationship emerged between eye movement abnormalities and clinical variables explored.

Basic symptoms and negative symptoms in the light of language impairment.

The Frankfurter Beschwerde-Fragebogen (FBF), assessing basic symptoms (B-S), and the Scale for the Assessment of Negative Symptoms (SANS) were administered to 30 patients satisfying DSM-III-R criteria for the diagnosis of schizophrenia. Considering the relationship between BS and negative symptoms (N-S), we identified the key role of the impairment of receptive and expressive language for the correlation of these two orders of phenomena.