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S.11.04 Can we identify subgroups for targeted adjunctive treatment?
S.12
Critical issues in clinical management of obsessive compulsive disorders
References Artigas, F., Romero, L., de Montigny, C. and Blier, P. (1996) Acceleration of the effect of selected antidepressant drags in major depression by 5-HTtA antagonists. Trends Neurosci. 19, 378-383. Bel, N. and Artigas, E (1996) In vivo effects of the simultaneous blockade of serotonin and norepinephrine transporters on serotonergic function. Microdialysis studies. Journal of Pharmacology and Experimental Therapeutics, 278, 1064-1072. Delgado, P.L., Chamey, D.S., Price, L.H., Aghajanian, G.K., Landis, H. and Heninger, G.R. (1990) Serotonin function and the mechanism of antidepressant action. Reversal of antidepressant-induced remission by rapid depletion of plasma tryptophan. Arch Gen Psychiatry, 47, 411--418.
~ C a n
we identify subgroups for targeted adjunctive treatment?
Michael T. Isaac. Department of Psychological Medicine, United Medical & Dental Schools, University of London (Guy's Campus), Suite 6, Lewisham Hospital, London, UK No antidepressant currently in use exerts a significant antidepressant effect for at least two to three weeks after the patient starts taking it. Open studies suggest that, for selective serotonergic re-uptake inhibitor (SSRI) antidepressants, this latency may be reduced when the drug is taken with the 5HTIA receptor blocker pindolol. In a recent randomised, placebo controlled double blind study at Guy's and Lewisham Hospitals, eighty out-patients (mean age 36 [range 19~55], 48 female, 32 male) were recruited, each patient receiving paroxetine (20 mg o.d.) plus, randomly, either pindolol (2.5 mg t.d.s.) or placebo for six weeks. Paroxetine (open label) was offered to all, patients for a further 18 weeks. Follow-up assessment on sixty-nine patients, took place at weeks 8, 16 and 24. Taken overall, the results showed a statistically significant acceleration, observable from day 4, of the antidepressant effect of paroxetine in the group receiving pindolol. In the intention to treat population, the divergence between pindolol and placebo groups disappeared by day 28, but persisted beyond day 42 in the per protocol group. In the longer term, patients originally treated with pindolol (n = 32) showed significantly better outcome at week 24, when compared with patients taking paroxetine alone, whether they complied fully with follow-up treatment or not. Compliance with follow-up paroxetine had a significant positive effect on outcome at weeks 16 and 24 in those originally treated with paroxetine alone (n = 37). Similar findings are apparent at one year. However, it is clear that the effect is not equally shared among all patients. We found, for example, that the combination worked less well in males over the age of thirty five years, and in males and females who had either a chronic history of dysthymia/depression or who were more severely depressed. We specifically excluded substance misusers. It may be relevant that our patients were reviewed twice weekly during the first two weeks of the study, and weekly thereafter. This was intended to permit the ascertainment of an early response to medication. It is becoming clearer that the 5HT1A receptor is subject to genetic polymorphism, and such differences may be highlighted by use of a 5HT1A receptor blocker. Moreover, the minus isomer and the mixed (plus/minus) enantiomer of pindolol appear to act differently (in rats, at any rate) in their activity as partial agonists of 5HT1A receptors. We examined personality variables in 48 consecutive subjects according to a short version (TCI-125) of Cloninger et al's self-rated Temperament & Character Inventory and correlated the results with clinical responses in the trial. The results suggest that high scores in the temperament dimension of Reward Dependence and low scores in the temperament dimension of Harm Avoidance had a better outcome at 6 weeks. Patients who had received paroxetine and pindolol during the trial and who reported high Novelty Seeking and low Harm Avoidance scores had a better outcome at 6 weeks and 6 months. We suggest that temperament factors may influence outcome of antidepressant treatment. These results suggest low dopamine and low serotonin transmission. Low serotonin levels may be associated with up regulation of serotonin receptors in the mesolimbic area, which can explain the rapid acceleration effect of pindolol in these patients. Pindolol has been shown in humans to increase prolactin levels (hence influencing dopamine levels), supposedly under the influence of the serotonergic system. However, the results in
S101
the pindolol group in our study perhaps suggest that this combination can also alter brain dopamine levels via the serotonergic system. Low serotonin levels have been reported in depressed patients. In our ~tudy, a low (<20 ng.ml -I ) baseline platelet 5HT was a~sociated with a poorer response to medication at day 42, compared with a 95% fall in platelet 5HT at day 7. There was an association between high baseline platelet 5HT and moderate depression, and low baseline platelet 5HT and severe depression at day 21. A previous history of more than two treated episodes of depression, or an initially severe (MADRS >34) baseline symptom profile was associated with less acceleration and poorer overall outcome. Chronicity as such did not predict lack of acceleration, although general outcome was less good. Many of the best responders were in employment and less than forty years old. The choice of SSRI may be important. But animal studies show no differences in the physiological or neurochemical consequences of pindolol in combination with any SSRI drugs, including fluoxetine. Moreover, in comparative and systematic studies, there is little to choose between the core antidepressant effects of fluoxetine and paroxetine (or other SSRI for that matter). In addition, acceleration of antidepressant effect is notoriously difficult to evaluate. It may seem an obvious point, but one must evaluate the patient during frequently during the early stages to show an early response; it is not enough to ask the patient at, say, ten or fourteen days ff he experienced an early effect before that point. A more rapidly acting antidepressant must not, of course, show only an early response; this must be sustained. Placebo control is essential, and some protocols insist on an one-week, placebo run-in phase in an attempt to control for a placebo response. This approach has merit, but a properly controlled study should be able to allow for early placebo effects, which, in any event, are usually not sustained. Developing more predictors of the response to antidepressants is a present and future challenge to research.
S.12 Critical issues in clinical management of obsessive compulsive disorders
I
•
Predictors of response
D. Marazziti. Institute of Psychiat~ University of Pisa, Italy In the last decades, consistent advancements have been raade in the synzhesis of new psychotropic drugs whose developments has, been paralleled ;and supported by the increased knowledge in Neuroscieuces. Therefore, psychopharmacological treatments have become more specific, although their effectiveness is not always restricted to clinical diagnostic entities, t~ut to symptom clusters or psychopathological dimensions. In spite of the continuous data efflux on the mode of actions of psychotropic drugs, on their spectrum of properties and side-effects, the choice of a drug is rather empyrical and no real predictors can currently be identified. However, the careful clinical observation of the patients, coupled with the present knowledge of the neurobiology of a given disorder and with the mechanisms underlying the effects of a drug should provide us some useful information. Some clinical indexes that seem to have a negative predictive value in obsessive-compulsive disorder (OCD), but which necessitate of further validation are: comorbidity with schyzotypal personality disorder, panic disorder, tic or Tourette's syndrome, early onset and chronic course. Our group investigated the possible usefulness of a peripheral serotonergic parameter, that is, platelet serotonin (5-HT) transporter, as a predictor of response in a group of 30 drug-free OCD patients. Platelet 5-HT transporter was measured by means of the specific binding of 3H-Paroxetine (3H-Par), before (tO) and after (tl) a 2-rnonth treatment with clomipramine, fluvoxamine and fluoxetine. Symptom severity was assessed with the Y-BOCS. The results showed that at baseline the patients had a decreased number of 3H-par binding sites which increased towards normal values after the treatments which was successful in most of that cases. The number of 3H-Par binding sites were significantly and negatively correlated with symptom severity at baseline, i.e., the lower
Critical issues in clinical management of obsessive compulsive disorders
References Artigas, F., Romero, L., de Montigny, C. and Blier, P. (1996) Acceleration of the effect of selected antidepressant drags in major depression by 5-HTtA antagonists. Trends Neurosci. 19, 378-383. Bel, N. and Artigas, E (1996) In vivo effects of the simultaneous blockade of serotonin and norepinephrine transporters on serotonergic function. Microdialysis studies. Journal of Pharmacology and Experimental Therapeutics, 278, 1064-1072. Delgado, P.L., Chamey, D.S., Price, L.H., Aghajanian, G.K., Landis, H. and Heninger, G.R. (1990) Serotonin function and the mechanism of antidepressant action. Reversal of antidepressant-induced remission by rapid depletion of plasma tryptophan. Arch Gen Psychiatry, 47, 411--418.
~ C a n
we identify subgroups for targeted adjunctive treatment?
Michael T. Isaac. Department of Psychological Medicine, United Medical & Dental Schools, University of London (Guy's Campus), Suite 6, Lewisham Hospital, London, UK No antidepressant currently in use exerts a significant antidepressant effect for at least two to three weeks after the patient starts taking it. Open studies suggest that, for selective serotonergic re-uptake inhibitor (SSRI) antidepressants, this latency may be reduced when the drug is taken with the 5HTIA receptor blocker pindolol. In a recent randomised, placebo controlled double blind study at Guy's and Lewisham Hospitals, eighty out-patients (mean age 36 [range 19~55], 48 female, 32 male) were recruited, each patient receiving paroxetine (20 mg o.d.) plus, randomly, either pindolol (2.5 mg t.d.s.) or placebo for six weeks. Paroxetine (open label) was offered to all, patients for a further 18 weeks. Follow-up assessment on sixty-nine patients, took place at weeks 8, 16 and 24. Taken overall, the results showed a statistically significant acceleration, observable from day 4, of the antidepressant effect of paroxetine in the group receiving pindolol. In the intention to treat population, the divergence between pindolol and placebo groups disappeared by day 28, but persisted beyond day 42 in the per protocol group. In the longer term, patients originally treated with pindolol (n = 32) showed significantly better outcome at week 24, when compared with patients taking paroxetine alone, whether they complied fully with follow-up treatment or not. Compliance with follow-up paroxetine had a significant positive effect on outcome at weeks 16 and 24 in those originally treated with paroxetine alone (n = 37). Similar findings are apparent at one year. However, it is clear that the effect is not equally shared among all patients. We found, for example, that the combination worked less well in males over the age of thirty five years, and in males and females who had either a chronic history of dysthymia/depression or who were more severely depressed. We specifically excluded substance misusers. It may be relevant that our patients were reviewed twice weekly during the first two weeks of the study, and weekly thereafter. This was intended to permit the ascertainment of an early response to medication. It is becoming clearer that the 5HT1A receptor is subject to genetic polymorphism, and such differences may be highlighted by use of a 5HT1A receptor blocker. Moreover, the minus isomer and the mixed (plus/minus) enantiomer of pindolol appear to act differently (in rats, at any rate) in their activity as partial agonists of 5HT1A receptors. We examined personality variables in 48 consecutive subjects according to a short version (TCI-125) of Cloninger et al's self-rated Temperament & Character Inventory and correlated the results with clinical responses in the trial. The results suggest that high scores in the temperament dimension of Reward Dependence and low scores in the temperament dimension of Harm Avoidance had a better outcome at 6 weeks. Patients who had received paroxetine and pindolol during the trial and who reported high Novelty Seeking and low Harm Avoidance scores had a better outcome at 6 weeks and 6 months. We suggest that temperament factors may influence outcome of antidepressant treatment. These results suggest low dopamine and low serotonin transmission. Low serotonin levels may be associated with up regulation of serotonin receptors in the mesolimbic area, which can explain the rapid acceleration effect of pindolol in these patients. Pindolol has been shown in humans to increase prolactin levels (hence influencing dopamine levels), supposedly under the influence of the serotonergic system. However, the results in
S101
the pindolol group in our study perhaps suggest that this combination can also alter brain dopamine levels via the serotonergic system. Low serotonin levels have been reported in depressed patients. In our ~tudy, a low (<20 ng.ml -I ) baseline platelet 5HT was a~sociated with a poorer response to medication at day 42, compared with a 95% fall in platelet 5HT at day 7. There was an association between high baseline platelet 5HT and moderate depression, and low baseline platelet 5HT and severe depression at day 21. A previous history of more than two treated episodes of depression, or an initially severe (MADRS >34) baseline symptom profile was associated with less acceleration and poorer overall outcome. Chronicity as such did not predict lack of acceleration, although general outcome was less good. Many of the best responders were in employment and less than forty years old. The choice of SSRI may be important. But animal studies show no differences in the physiological or neurochemical consequences of pindolol in combination with any SSRI drugs, including fluoxetine. Moreover, in comparative and systematic studies, there is little to choose between the core antidepressant effects of fluoxetine and paroxetine (or other SSRI for that matter). In addition, acceleration of antidepressant effect is notoriously difficult to evaluate. It may seem an obvious point, but one must evaluate the patient during frequently during the early stages to show an early response; it is not enough to ask the patient at, say, ten or fourteen days ff he experienced an early effect before that point. A more rapidly acting antidepressant must not, of course, show only an early response; this must be sustained. Placebo control is essential, and some protocols insist on an one-week, placebo run-in phase in an attempt to control for a placebo response. This approach has merit, but a properly controlled study should be able to allow for early placebo effects, which, in any event, are usually not sustained. Developing more predictors of the response to antidepressants is a present and future challenge to research.
S.12 Critical issues in clinical management of obsessive compulsive disorders
I
•
Predictors of response
D. Marazziti. Institute of Psychiat~ University of Pisa, Italy In the last decades, consistent advancements have been raade in the synzhesis of new psychotropic drugs whose developments has, been paralleled ;and supported by the increased knowledge in Neuroscieuces. Therefore, psychopharmacological treatments have become more specific, although their effectiveness is not always restricted to clinical diagnostic entities, t~ut to symptom clusters or psychopathological dimensions. In spite of the continuous data efflux on the mode of actions of psychotropic drugs, on their spectrum of properties and side-effects, the choice of a drug is rather empyrical and no real predictors can currently be identified. However, the careful clinical observation of the patients, coupled with the present knowledge of the neurobiology of a given disorder and with the mechanisms underlying the effects of a drug should provide us some useful information. Some clinical indexes that seem to have a negative predictive value in obsessive-compulsive disorder (OCD), but which necessitate of further validation are: comorbidity with schyzotypal personality disorder, panic disorder, tic or Tourette's syndrome, early onset and chronic course. Our group investigated the possible usefulness of a peripheral serotonergic parameter, that is, platelet serotonin (5-HT) transporter, as a predictor of response in a group of 30 drug-free OCD patients. Platelet 5-HT transporter was measured by means of the specific binding of 3H-Paroxetine (3H-Par), before (tO) and after (tl) a 2-rnonth treatment with clomipramine, fluvoxamine and fluoxetine. Symptom severity was assessed with the Y-BOCS. The results showed that at baseline the patients had a decreased number of 3H-par binding sites which increased towards normal values after the treatments which was successful in most of that cases. The number of 3H-Par binding sites were significantly and negatively correlated with symptom severity at baseline, i.e., the lower