S.26.05 Structural brain imaging: Relationship to treatment response and clinical outcome of schizophrenia

S.26

S 130

Psychopharmacoiogy and brain-imaging

treated with classical neuroleptics and clozapine - relation to extrapyramidal side effects. Arch Gen Psychiatry 49:538-544 [2] Farde L, Suhara T. Nyberg S, Karlsson P, Nakashima Y, Hietala J, Halldin C (in press). A PET-study of [H C]FLB 457 binding to extrastriatal D2-dopamine receptors in healthy subjects and antipsychotic drug treated patients. Psy-

chopharmacology.

[3] Halldin C, Farde L, H0gberg T, Suhara T, Karlsson P, Nakashima Y, Swahn C (1995)[HC]FLB457, a selective PET radioligand for examination of extrastriatal dopamine D2 receptors. Preparation, metabolite studies and in vivo distribution in the monkey brain using PET. J Nucl. Med. 36: 1275-1281. [4] Loc'h C, HaUdin C, Botflaender M, Swahn C, Mresco R, Maziere M, Farde L, Maziere B (1996)Preparation of [76Br]FLB 457, [76Br]FLB 463 and [76Br]NCQ 115 for examination of striatal and extrastriatal dopamine D2-receptors with PET. Nucl. Med. Biol. 23:813-819

•

EEG/ERP-mapping as a tool in psychopharmscology

B. Saletu, P. Anderer, R. Pascual-Marqui, H.V. Semlitsch. Department of

Psychiatry, University of Vienna, Austria, The KEY lnstitute for Brain-Mind Research, Department of Psychiatry, University Hospital Zurich, Switzerland Mapping of the electroencephalogram (EEG) and event-related potentials (ERP) are readily and widely available, low cost, non-invasive, high-time resolution methods for studying objectively and quantitatively the effects of drugs on brain function in normals as well as patients with mental disorders. Classification of drugs by EEG/ERP-mapping: Representative drugs of the main psychopharmacological classes induce - as compared with placebo - significant and typical changes in normal human brain function, as objectified by pharmaco-EEG maps. Typical pharmaco-EEG maps have been described after sedative neuroleptics (e.g. 50 mg chlorpromazine), non-sedative neuroleptics (3 mg haloperidol), sedative antidepressants (75 mg imipramine), non-sedative antidepressants (20 mg citalopram), daytime tranquilizers (30 mg clobazam), night-time tranquilizers (2 mg lorazepam) psychostimulants (20 mg amphetamine), nootropics (600 mg pyritinol). Also regarding ERP, representative drugs of the main psychopharmacological classes (3 mg haloperidol, 20 mg citalopram, 2 mg lorazepam and 20 mg methylphenidate) induce differential effects in latencies and amplitudes of non-target N1 and P2 components reflecting automatic information processing and target P3 components reflecting cognitive information processing capacity and stimulus evaluation time. EEG/ERP-mapping in human psychopharmacology (phase I): Based on the above described patterns, EEG-mapping may be utilized at an early stage of drug development (phase I) to determine whether a newly developed compound is CNS effective at all, as compared with placebo, and what its clinical efficacy eventually will be like. A further prominent feature of pharmaco-EEG mapping is the additional potential of the method to determine cerebral bioavailability or effect-kinetics, e.g. at which dosage a drug acts (minimal CNS effective dosage, dose-efficacy relations, etc.), at which time it acts (onset, maximum and end of its central effect at the target organ) and to evaluate equipotency of different galenic formulations of a compound. Although to a lesser extent the ERPs have also been applied to answer similar questions. Classification of mental disorders: Intriguingly, EEG drug effects in normals are quite often opposite to EEG differences between patients and normals (e.g. anxiolytics produce EEG changes opposite to GAD alterations). In the last decade, EEG-mapping has been applied to characterize brain dysfunctions in drug-free patients with schizophrenia exhibiting predominantly minus or plus symptomatology, major depression, generalized anxiety disorder, agoraphobia, obsessive compulsive disorder, vascular (MID) dementia, dementia of the Alzheimer type (SDAT) and alcohol dependence. Different mental disorders result in different EEG maps, a fact which can be utilized for diagnostic purposes. Quantitative ERP descriptors are also sensitive indicators of brain dysfunction in patients with psychiatric illnesses, specifically regarding cognitive information processing. EEG/ERP-mapping in pharmacopsychiatry (phase H-IV): EEG mapping has been found useful also in pharmacopsychiatry, both in demonstrating drug effects at the target organ, the human brain, and in assisting to identify therapeutic efficacy, as for instance with nooptropic compounds, aiming to improve vigilance. Moreover, one may predict and monitor

therapeutic efficacy of drugs in individual patients and demonstrate normalisation of brain function. ERPs have been employed in a similar manner, with special emphasis on cognitive information processing. Outlook on 3-dimensional approaches: One of the drawbacks of EEG/ERP-mapping was its 2-dimensionality, describing brain function in the outer cortical structures of the brain without considering deeper subcortical structures. However, electrical fields measured on the scalp are created by electrical currents within the brain, which can be described simplistically as dipoles. In dipole source estimation, one calculates the location, strength and direction of one or more equivalent dipoles. Still, a number of assumptions must be made about the head and sources, and new location models, such as those based on the minimum norm approach or those utilizing temporal information and introducing spatio-temporal constraints did not overcome the basic difficulty - namely that they were not truly 3-dimensional neuroimaging methods. Pascual-Marqui et al. recently presented a novel approach, computing a current distribution throughout the full brain volume called the low resolution electro-magnetic tomography (LORETA). The method assumes diat neighbouring neurons are simultaneously and synchronously activated. This basic assumption rests on evidence from single cell recordings in the brain, demonstrating strong synchronization of adjacent nem'ons. The computational task was to select the smoothest of all possible 3-dimensional current distributions, a task that is a common procedure in generalized signal processing. The result is a true 3-dimensional tomography with the characteristic that location is preserved with a certain amount of dispersion, i.e. it has a relatively low spatial resolution. Recent investigations on changes in latency and amplitude of acoustic N1 and P3 ERP components over the normal aging process as well as before and after nootropic therapy in age associated memory impairment provided physiologically meaningful results and offered new hypotheses on the location of higher cognitive functions in the brain - eventually identifying structures modified in their function by drugs.

•

Structural brain imaging: Relationship to treatment response and clinical outcome of schizophrenia

A. Vita. lnsitute of Psychiatry, University of Milan, Italy The study of cerebral structural abnormalities is one of the most active and interesting fields of biological psychiatry research. Magnetic Resonance Imaging (MRI) studies have now demonstrated cerebral[ structural abnormalities relative to cerebral ventricles, temporal lobe, limbic structures, frontal lobe and basal ganglia (Chua and McKenna, 1995). Neuromorphological abnormalities have been correlated with symptomatological patterns, neuropsychological performance, premorbid functioning and duration of illness. All of these measures are considered to be predictors of neuroleptic response and outcome of schizophrenia. The relationship of brain morphology to treatment response and clinical outcome of the disease is still a controversial issue, and some methodological questions remain unresolved: the high number of potential correlations between morphological and outcome variables increases the probability of chance findings; the fact that patients showing a more severe psychopathology at the onset of the disease, can lead to the false observations either of a better response, if this is evaluated as the percent of symptoms impovement relative to the baseline, or of a worse response, if evaluated as the reaching of a given threshold. In this paper we report data obtained in one of our recent MRI studies, aimed at investigating the association between neuromorphological variables, quantitatively assessed, and symptomatological course and outcome of schizophrenic patients. A group of 15 schizophrenic subjects (DSM III-R), 9 males and 6 females, mean age 25.6 ± 6.3 years, mean duration of illness 1.6 ± 1.2 years at the beginning of the study, underwent cerebral MRI with a 0.5 Tesla GE MR Max system. Morphological analyses were performed on coronal slices, 5 mm thick, obtained with a Tl-weighted spin echo sequence (TR 600 ms; TE 25 ms). Image analysis was performed with a RAS 2000 computerized image analysis system (Amersham Int.). We analyzed volumes of prefrontal lobes (PFL), temporal lobes (TL) and lateral ventricles. White and gray matter were considered together. Analyses were performed for ratios of regional volumes to total cranial volume.

S.27 Neuropsychopharmacology in child psychiatry

$131

S.26.05: Table 1. Brain regional dimensions in good and poor symptomatical outcome schizophrenic patients Strauss-Carpenter Scale

(poor/good outcome) SC Hospital Stay - poor outcome - good outcome SC Useful Employ - poor outcome - good outcome SC Social Contacts - poor outcome - good outcome SC Sev. of Symptoms - poor outcome - good outcome SC Total Score - poor outcome -good outcome

Brain Regional Dimensions ]

Right Ventricles

Left Ventricles

Right Temporal

Left Temporal

Right Prefrontal

Left Prefrontal

6.2 4- 3.9 5,9 4- 4.2

6.4 4- 2.4 5.7 4- 4.7

61.4 4- 17.2 60.9 4- 14.3

58.6 4- 11.2 56.4 4- 16.7

48.5 4- 11.2 49.6 4- 7.4

51.1 4- 13.6 53.4 4- 9.5

6.7 4- 3.4 6.1 4- 2.2

7.1 4- 3.3 6.6 4- 5.1

62.5 4- 16.9 59.9 4- 15.3

60.1 4- 12.3 58.7 4- 15.6

47.6 4- 12.2 52.8 4- 9.4

52.4 4- 14.7 51.7 4- 9.7

6.8 4- 1.8 6.4 4- 3.6

6.0 4- 2.7 5.9 4- 4.1

62.6 4- 16.2 61.3 4- 12.5

63.4 4- 10.2 62.7 4- 15.2

54.6 4- 9.3 55.9 4- 11.4

51.6 4- 13.8 57.5 4- 11.2

5.7 4- 3.0 5.9 4- 3.2

5.9 4- 2.6 6.2 4- 2.2

61.4 4- 17.2 60.5 4- 14.3

59.3 4- 15.2 59.4 4- 9.4

40.9 4- 17.4 62.8 4- 9.5 °

39.9 4- 16.3 58.1 4- 15.5

6.5 4- 2.9 6.3 4- 2.3

6.4 4- 2.0 6.2 4- 4.3

64.5 4- 12.6 62.9 4- 13.6

62.3 4- 13.2 61.9 4- 11.3

37.6 4- 16.2 62.9 4- 11.4*

37.4 4- 15.7 58.7 4- 14.5

i Ratios to total intracranial volume. * F = 5.16, df = 1,12, p = 0.04. r F = 6.2, df = 1,12, p = 0.036. No statistical significance emerged for covariates, within subjects factors and interactions.

All patients were receiving antipsychotic treatment (5.2 -+- 3.7 mg/day of halopreridol equivalents). Outcome was evaluated after 24 months from the beginning of the study using the Strauss-Carpenter Outcome Scale. Patients were then divided, considering the median score value, in two groups (good and poor outcome) for each item of the scale. We performed three separate multivariate analyses of covariance (MANCOVA), where variables in analysis were frontal lobe, temporal lobe and lateral ventricular volumes; the between-subjects variation factor was "good" or "poor outcome" in each of the Strauss-Carpenter item scores; the covariation factor was the baseline evaluation of the same scores; finally, side (right vs. left) was the within-subjects factor. No significant effects emerged for lateral ventricular and temporal lobe volumes. As for prefrontal lobe volume, analyses pointed out that patients with different outcomes in the areas: "severity of symptoms" and "total Strauss-Carpenter score" has different PFL volumes (respectively F = 5.16, d f = 1,12, p = 0.04 and F = 6.2, df= 1,12.p = 0.036). As expected, patients showing worse outcome had significantly smaller PFL volumes (Table 1). Our results indicate a predictive validity of cerebral morphology on symptomatological course and outcome of schizophrenia in neuroleptic treatment. Even if an earlier meta-analysis (Friedman et a1.,1992) on the relationship of structural brain imaging parameters to antipsychotic treatment response did not demonstrate a full statistical significance for the whole sample of studies considered, several studies and some of the more recent ones reported data in line with our results. Moreover, our present findings are consistent with earlier reports by our research group indicating neuropathology as a predictor of clinical outcome of both acute, schizophreniform disorder (Vita et al., 1991a) and chronic schizophrenia (Vim et al., 199 lb).

References Chua SE, McKenna PJ. Schizophrenia - a brain disease? A critical review of structural and functional cerebral abnormality in the disorder. Br J Psychiatry 1995; 166: 563-582. Friedman L. Lys C, Schulz SC. The relationship of structural brain imaging parameters to antipsychotic treatment response: a review. J Psychiatr Neurosci 1992; 17 (2): 42-54. Vita A, Giobbio GM, Garbarini M, et al. Prognostic value of ventricular enlargement in acute schizophreniform disorder. Lancet 1991a; II: 1458. Vita A, Dieci M, Gobbio GM, et al. CT scan abnormalities and outcome of chronic schizophrenia. Am J Psychiatry 1991b; 148: 1577-1579.

S.27 Neuropsychopharmacology in child psychiatry

[•

Psychopharmacology of impulsivity and aggression in childhood and adolescence

E. Taylor. MRC Child Psychiatry Unit, Department of Child and AdolescentPsychiatry, London, UK The value of stimulant drugs in treating childhood disorders of "hyperactivity" - ie impulsive, restless and inattentive behaviour traits - is now well established by scores of randomised controlled ~ials and several metaanalyses. Children who meet the ICD-10 criteria for hyperkinetic disorder (HD) should have a treatment plan that includes the reduction of hyperactive behaviour as one of the goals. A multimodal treatment approach will usually be needed. European guidelines have been drawn up (Taylor et al 1997). This paper will review o u t s ~ a d i n g problems where research is in progress. C h o i c e o f d r u g : All three stimulants - methylphenidate, d-amphetamine and pemoline - have broadly similar effects on children's behaviour: I:hey reduce hyperactive behaviour, enhance several aspects of information processing, and increase on-task attentiveness. Methylphenidate will usually be the first choice; but dexamphetamine may be preferred if the child has epilepsy. Pemoline is not a controlled drug, and is sometimes preferred for this reason and because of its somewhat longer duration of action; but it carries the hazard of hepatotoxicity. Any of 'these drugs may ,succeed when the others have failed. L e n g t h o f t r e a t m e n t : Evidence of long-term value is limited; but the aim should be to maintain medication until the child's maturation and learning of cognitive skills make medication unnecessary. Periodically, approximately annually, there should be a gradual withdrawal of med:tcation over a period of two weeks to assess whether there is indeed a continuing need for medication. Drug holidays are not required routinely unless the child's growth has been affected. T r e a t i n g m i l d e r e a s e s o f A D H D : Medication is not always needed for children with lesser degrees of hyperactivity - ie those with a DSM-IV diagnosis of Attention Deficit/Hyperactivity Disorder (ADHD), but not HD. Underlying causes such as learning disabilities, hearing impairment, family stresses, attachment disruptions and emotional disorders should be carefully sought. Indications for medication in this group will usually arise only if the problems have not resolved with approaches designed to remove environmental causes or treat psychologically. There may be a temptation to rely unduly on the effect of medication and to use it for mild cases where educational intervention and psychological treatment would be sufficient. T r e a t m e n t o f p r e s c h o o l c h i l d r e n : Methylphenidate is officially not recommended below the age of 6, though it is hard to see why the manufacturers have taken this line from the scientific evidence and dexamphetamine is licensed down to the age of 3 years. Clinicians should