Paola Brovedani

The hippocampus, neurotrophic factors and depression: Possible implications for the pharmacotherapy of depression

Depression is a prevalent, highly debilitating mental disorder affecting up to 15% of the population at least once in their lifetime, with huge costs for society. Neurobiological mechanisms of depression are still not well known, although there is consensus about interplay between genetic and environmental factors. Antidepressant medications are frequently used in depression, but at least 50% of patients are poor responders, even to more recently discovered medications. Furthermore, clinical response only occurs following weeks to months of treatment and only chronic treatment is effective, suggesting that actions beyond the rapidly occurring effect of enhancing monoaminergic systems, such as adaptation of these systems, are responsible for the effects of antidepressants.Recent studies indicate that an impairment of synaptic plasticity (neurogenesis, axon branching, dendritogenesis and synaptogenesis) in specific areas of the CNS, particularly the hippocampus, may be a core factor in the pathophysiology of depression. The abnormal neural plasticity may be related to alterations in the levels of neurotrophic factors, namely brain-derived neurotrophic factor (BDNF), which play a central role in plasticity. As BDNF is repressed by stress, epigenetic regulation of the BDNF gene may play an important role in depression. The hippocampus is smaller in depressed patients, although it is unclear whether smaller size is a consequence of depression or a pre-existing, vulnerability marker for depression. Environmental stressors triggering activation of the hypothalamic-pituitary-adrenal axis cause the brain to be exposed to corticosteroids, affecting neurobehavioural functions with a strong downregulation of hippocampal neurogenesis, and are a major risk factor for depression. Antidepressant treatment increases BDNF levels, stimulates neurogenesis and reverses the inhibitory effects of stress, but this effect is evident only after 3–4 weeks of administration, the time course for maturation of new neurons. The ablation of hippocampal neurogenesis blocks the behavioural effects of antidepressants in animal models.The above findings suggest new possible targets for the pharmacotherapy of depression such as neurotrophic factors, their receptors and related intracellular signalling cascades; agents counteracting the effects of stress on hippocampal neurogenesis (including antagonists of corticosteroids, inflammatory cytokines and their receptors); and agents facilitating the activation of gene expression and increasing the transcription of neurotrophins in the brain.

Open trial of risperidone in 24 young children with pervasive developmental disorders

OBJECTIVE To describe tolerability and efficacy of risperidone in very young children with pervasive developmental disorders. METHOD Twenty-four children aged 3.6 to 6.6 years (mean 4.6 years +/- 8 months) enrolled during 1999 and 2000 participated in a 16-week open-label trial with risperidone monotherapy. Outcome measures included the Childrens Psychiatric Rating Scale (CPRS), Childhood Autism Rating Scale (CARS), Clinical Global Impression-Improvement (CGI-I), and Childrens Global Assessment Scale (C-GAS). RESULTS Two subjects did not complete the trial because of side effects. The optimal dose was 0.5 mg/day. After the treatment a 21% improvement in CPRS and a 14% improvement in CARS total scores was found. Items related to behavioral control (hyperactivity, fidgetiness, rhythmic motions) and affect regulation (lability of affect, angry affect) improved more than 25%. Based on improvement of at least 25% on the CPRS and a score of 1 or 2 on the CGI-I, eight subjects were considered responders. Functional impairment (C-GAS) improved more than 25%. Thirteen subjects (54%) were free of any side effects; in the other participants risperidone was well tolerated. Only three subjects had a weight gain greater than 10%. CONCLUSIONS Low-dose risperidone may positively affect symptoms in young autistic children, improving disruptive/hyperactive behavior and affective dysregulation. Further controlled studies in this age group are warranted.

Is interhemispheric transfer time related to age? A developmental study

In simple visuomotor reaction time tasks, the difference between reaction time (RT) in the uncrossed hand/hemifield condition from RT in the crossed hand/hemifield, known as CUD (crossed-uncrossed difference), has been interpreted as reflecting interhemispheric transmission time (IHTT). Several studies in normal adults have found a CUD of a few milliseconds (3-4), while an abnormally long CUD has been reported in patients who underwent a surgical section of the corpus callosum or in congenital acallosal subjects. The corpus callosum, which is the most important structure for interhemispheric transfer of information, completes its myelination approximately by age ten. It has been hypothesized that the functional maturity of the corpus callosum coincides with the termination of the myelination cycle. No developmental study has focused on the development of IHTT, in relation to callosal maturation. The purpose of our study has been to investigate the development of interhemispheric transfer of visuomotor information in children aged seven to eleven, using a simple RT task with lateralized visual stimuli. The results indicate an age-related decrease of CUD, which we interpret as reflecting the maturation of the corpus callosum during childhood years.

Atypical language lateralization and early linguistic development in children with focal brain lesions.

The effects of congenital, unilateral, focal brain lesions on early linguistic development and hemispheric lateralization for language were investigated longitudinally in 24 preschool children with hemiplegia (14 males, 10 females), 12 with left hemisphere damage (LHD) and 12 with right hemisphere damage (RHD). A comprehensive linguistic assessment was performed at 2 and 3 years of life; cerebral lateralization for language was measured by the Fused Dichotic Words Listening Test. An early left-side specificity for language was indicated by the presence of lexical and grammatical delay in most children with LHD. In the dichotic listening test all 12 children with LHD showed a shift of language lateralization from the left to the right hemisphere. Atypical lateralization coefficients (lambda), i.e. values falling more than two standard deviations from the mean of a normative sample, were associated with a delay in lexical and grammatical development, especially after LHD. In addition, cortical-subcortical-periventricular lesions rather than solely periventricular damage, and larger lesions rather than small, were associated with the most atypical lateralization coefficients, irrespective of lesion side. Results of this study suggest that language and lateralization data are closely related and that reallocation of language functions in alternative regions of the brain has a cost in terms of a slow rate of language acquisition.

Abnormal Phonologic Processing in Familial Lateral Temporal Lobe Epilepsy Due to a New LGI1 Mutation

Summary:  Purpose: Autosomal dominant lateral temporal lobe epilepsy (ADLTLE) is a rare familial epilepsy with onset in adolescence or early adulthood, associated with mutations of LGI1 in most families. We describe the clinical, neuropsychological, and molecular genetic study of a new ADLTLE Italian family.

Temperament in Adolescents with Anxiety and Depressive Disorders and in Their Families

Aim of this study was to investigate whether specific temperamental features were associated with anxiety and depressive disorders in adolescents, in their siblings and in their parents. Thirty adolescents with Anxiety disorders and 25 with both Anxiety and Depressive disorders were compared to 25 adolescents with learning disorders and to 28 normal subjects. Temperament in subjects and relatives was assessed by their parents with the EAS questionnaire. Subjects with Anxiety and Anxiety-Depression and their siblings showed higher scores on Emotionality and Shyness than Learning Disability and Normal subjects. Mothers and fathers of subjects from the Anxiety-Depression group had the highest Emotionality score. These findings suggest that both Emotionality and Shyness are prominent temperamental features in adolescents with anxiety with or without depression, and in their parents and siblings.

Assessment of Anxiety and Depression in Adolescents with Mental Retardation

This report examines the concurrent validity of different informant and self-report assessment instruments of psychopathology, both general and specific for anxiety and/or depression, in referred mentally retarded adolescents with a depressive and anxiety disorders, according to DSM IV criteria. A consecutive, unselected sample of 50 mildly and moderate mentally retarded adolescents (29 males and 21 females, aged 11.8 to 18 years, mean age 15.1) were assessed using standardized assessment techniques: Psychopathology Instrument for Mentally Retarded Adults (PIMRA) (informant version) (total score, affective and anxiety subscales), Child Behavior Checklist (CBCL) (informant version) (total score, internalizing and externalizing scores, anxiety-depression scale), Zung Self-Rating Depression Scale and Zung Self-Rating Anxiety Scale. Patterns of correlation among measures were calculated. PIMRA and CBCL total scores were closely intercorrelated. Internalizing and externalizing scores of CBCL were not intercorrelated, but they both correlated with CBCL and PIMRA total scores. Anxiety measures were positively correlated; they correlated with PIMRA and CBCL total scores, as well as with the internalizing score of CBCL. Depression measures were not correlated; their correlation with more general measures of psychopathology was weak. Clinical implications of these findings are discussed.

Pharmacotherapy of major depressive disorder in adolescents

Importance of the field: At any one time, major depressive disorder (MDD) affects 4 – 6% of adolescents. When untreated, MDD leads to a high immediate and subsequent suicide risk, long-term chronicity and a poor psychosocial outcome. Whereas psychotherapy can be effective in mild depression, it seems to be less effective in moderate and severe depression. However, although the use of antidepressants increased markedly during the 1990s, in recent years it has decreased as a result of concerns regarding the emergence of suicidality during antidepressant treatment. Areas covered in this review: Are antidepressants truly effective? What is the relationship between different treatments for depression – psychotherapy and pharmacotherapy – alone or in combination? Can antidepressants increase the risk of suicide in some adolescents? Can antidepressants reduce suicide risk in suicidal adolescents? What the reader will gain: There is evidence that selective serotonin reuptake inhibitors (SSRIs) can improve adolescent depression better than placebo, although the magnitude of the antidepressant effect is ‘small to moderate’, because of a high placebo response. The SSRI with the best rate of response compared to placebo is fluoxetine. The increased risk of suicidality in adolescents, compared to adults, is weak but consistent across most studies. However, epidemiological studies do not support a relationship between use of antidepressants and suicide rate. Take home message: A cautious and well-monitored use of antidepressant medications is a first-line treatment option in adolescents with moderate to severe depression. Low rates of remission with current treatment strategies indicate that further research in both psychotherapy and pharmacotherapy is warranted.

Neuropsychological Findings in Idiopathic Occipital Lobe Epilepsies

Summary:  Purpose: We reviewed the clinical charts of 22 patients (mean age 12 years) with idiopathic occipital lobe epilepsies (IOLE) to verify the presence of visuoperceptual difficulties.

A 7 Mb Duplication at 22q13 in a Girl With Bipolar Disorder and Hippocampal Malformation

We identified a duplication of 22q13.1‐q13.2 in a 10‐year‐old girl and demonstrated that this duplication was the recombinant product of a maternal intrachromosomal insertion. Phenotypic characteristics included prominent forehead, small low‐set ears, hypertelorism, epicanthal folds, small palpebral fissures, short philtrum, and syndactyly. MRI of the brain revealed high signal abnormalities in the periventricular white matter, a hypoplastic corpus callosum, under‐rotated hippocampus on the left and atrophic hippocampus on the right. Since age 5, the childs behavior has shown cyclic maniacal episodes with severely disorganized mood and behavior. Psychiatric and cognitive assessment led to a diagnosis of bipolar disorder not otherwise specified, manic episodes, attention deficit hyperactivity disorder and moderate mental retardation. Array‐CGH revealed an interstitial duplication of 6.9 Mb at chromosome 22q: dup(22)(q13.1q13.2). FISH using BAC clones confirmed the array‐CGH results and demonstrated that the duplication was inverted. G‐banding analysis in the propositas mother revealed a banding pattern suggestive of an intrachromosomal insertion, as demonstrated by dual‐color FISH with BACs that were duplicated in the proposita and multicolor‐banding (MCB) based on microdissection derived region‐specific libraries for chromosome 22. Our findings suggest that in both seemingly de novo deletions and duplications, the parent transmitting the imbalance should be investigated for possible balanced rearrangements. This report reinforces previous evidence that chromosome imbalances, and thus gene dosage effects, may be at the basis of some psychiatric disorders. Stringent correlations between submicroscopic imbalances, specific behavioral phenotypes and brain imaging will possibly help in dissecting complex behavioral traits.