S.22.01 How should we treat mania?

S.22 Psychopharmacoiogy of bipolar disorder

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PNU-101387 (S( - )-4- [4- [2-(isochroman- 1-yl)ethyl]piperazin- 1-yl]benzene sulfonamide (2). This compound shows a high degree of selectivity for the human D4 receptor in in vitro binding assays (Ki = 4 nM) with Ki's for other monoaminergic receptors exceeding 1 /.tM. PNU-101387 was shown to lack intrinsic efficacy in a series of in vitro assays (e.g. mitogenesis and cAMP) based on stably expressed D4 receptors while it readily blocked the effects of dopamine agonists in these assays. In behavioral assays in rats or mice, PNU-101387 was found to be inactive over a large dose range. Thus, the drug failed to affect motor activity in actively exploring, habituated or monoamine depleted animals and the conditioned avoidance response in the rat was also not affected. PNU-101387 also failed to affect post mortem brain levels of monoamines and their metabolites in the rat and it was also inactive regarding DA-release and DA cell firing as measured by microdialysis and electrophysiological experiments, respectively. When tested in putative animal models of psychosis, PNU-101387 failed to antagonize d-amphetamine hyperactivity or to block the disruption of prepulse inhibition (PPi) induced by PCP in the rat. However, as seen previously with atypical neuroleptics, PNU-101387 potently increased the expression of c-fos mRNA in the medial prefrontal cortex and NGFI-A mRNA in the lateral septum and the nucleus accumbens shell. In line with this "atypical profile" PNU-101387 did not induce the immediate early gene expression in the striatum, The fact that PNU-101387 also failed to induce catalepsy, affect striatal acetylcholine levels or affect plasma prolactin levels strongly suggest that this compound will lack the traditional side-effects induced by neuroleptics. In a chronic study in rats, PNU-101387 was found to block the locomotor sensitization induced by d-amphetamine. Interestingly, PNU-101387 was also able to antagonize the sensitization-induced reduction in immediate early genes in the medial prefrontal cortex, the neostriatum and the nucleus accumbens. The clinical relevance of these findings will be revealed in ongoing clinical trials in schizophrenia.

References [ 1] Waters, N., et al. The dopamine D3 receptor; A postsynaptic receptor inhibitory on rat locomotor activity..L Neural. Transm.94, 11-19, 1993. [2] Merchant K.M., et al. Pharmacological characterization of U-101387, a dopamine D4 receptor selective antagonist. J. PharmacoL Exp. Ther 279, 1392-1403, 1996.

similar receptor profiles. However, it should be noted that the number of other receptors, e.g. alpha-l, alpha-2, 5-HT2, H1, MI, D1 are blocked as well in different affinities by both substances and the interaction with some of these receptors is discussed in relation to the clinical profile of the substance as well. Many of the new antipsychotics like sertindole, ziprasidone, zotepine, risperdal, or seroquel show s:knilar or slightly different receptor profile. The modulation of these various transmitter receptors depends on dosage and pharmacokinetics meaning drug availability and pharmacodyarnic aspects, which have to be considered as they are individually different. In summary, most of the new antipsychotics show clinical efficacy considering the outcome criteria improvement of positive or negative symptoms. To determine possible differences of the new atypical antipsychotics other criteria of efficacy have to be considered. This can be the early onset of clinical improvement, a better compliance, quality of life effects, differences in target symptoms of the psychosis, and the identification of subgroups of schizophrenic patients who respond to the specific compound. An attempt wil]t be undertaken to compare various new antipsychotics in relation to these criteria.

References [1] Bailey PE, McKenna PJ (1990) Pharmacological approaches to the treatment of schizophrenia: the concept of "atypically". Triangle 29:133-139 [2] Seeman P (1992) Dopamine receptor sequences. Therapeutic levels of neuroleptics occupy D2 receptors, clozapine occupies D4. Neuropsychopharmacology 7:261-284 [3] Sokoloff P. Gubos B, Martrtres MP, Booouthenet ML, Schwartz JC (1990) Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. Nature 347: 146-15l [4] Van Tol HHM. Bunzow JR, Guan H-C, Sunahara RK, Seeman P, Niznik HB, Civelli O (1991) Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine. Nature 350:610-614

S.22 Psychopharmacology of bipolar disorder ~ H o w

should we treat mania?

Guy Goodwin. University of Oxford Department of Psychiatry,

Warneford Hospital, Oxford, United Kingdom

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Clinical importanceof D3/D4 receptorantagonists

M. Ackenheil, T. Messer, N. Miiller. Psychiatric Hospital, University of

Munich, Munich, Germany The development of new antipsychotic drugs has led to enormous progress in the treatment of schizophrenic patients. In general, a good clinical response including both positive and negative symptoms is claimed with a low risk for extrapyramidal motor side effects. These are the major characteristics of the so-called atypical antipsychotics (Bailey and McKenna, 1990). The exploration of the potential mechanism of antipsychotic drug action is a major challenge for research for better understanding the pathophysiology of schizophrenic symptoms and their specific treatment. Aside from blocking postsynaptic D2 receptors as the principle target of classical neuroleptics (Seeman 1992), new atypical antipsychotics are additionally targeting the other D2-1ike receptors, D3 and D4 receptors, which were recently discovered (Van Tol et al. 1991; Sokoloffet al. 1990) and explored. It was the hope that one of these three receptors would be a candidate gene for schizophrenia, but conclusive results were not shown. So far, the clinical importance of these new receptors for the pathophysiology of schizophrenia is unknown. Altough both receptors are highly polymorphic, especially the D4 receptor gene at three sites, the N-terminus of the receptor, the second putative transmembrane domain and the third cytoplasmatic loon, no significant difference in clinical response to clozapine was found. O-substituded benzamides like sulpiride and amisulpride are the most selective D3/D2 blocking antidopaminergic drugs which help to explore their characteristic pharmacological and clinical profiles. Clozapine, on the other hand, has a very high affinity for the D4 receptor at levels that correspond to therapeutic doses suggesting that this receptor mediates the clinical effect of clozapine. Other new compounds like olanzapine have

The treatment of acute mania and the management of long term risks of recurrence has for many years relied upon the use of lithium. We are entering an era where the use of lithium may be increasingly questioned. The reasons why this is so will be described in relation to the following problems: the efficacy of lithium and its effectiveness in every day practice, the neurotoxicity of lithium and the increasing competition from alternative mood stabilisers. The efficacy of lithium was established in the 1970s in two large and convincing randomised controlled trials. There is no reason really to question their findings although as with most trials there are small difficulties. The real problem has been why it has proved difficult to translate the size of effects seen in these trials into an advantage for patients treated under ordinary clinical conditions. This paradox was first highlighted by Dickson and Kendell (1986) and was taken forward by Mander (1986) who showed that lithium discontinuation was associated with a high risk of re-admission with manic illness in bipolar patients. Review of the literature by Suppes et al (1991) showed that in 14 studies involving 250 patients with bipolar 1 disorder, more than 50% of new illness occurred within 10 weeks of stopping treatment. The length of treatment preceding the discontinuation was variable but averaged about 13 months. This finding has important implications for the use of lithium which have been outlined previously (Goodwin 1994). If the risk of manic recurrence is assumed to be between 30%-50% for the 3 months after stopping lithium and the withdrawal effect manifests it:self essentially as a new episode of illness the implications are very important. In a nutshell they mean that lithium should be used for at least 2 years for prophylaxis before any benefit can be experienced by the patient. Failing to use lithium for that long results in a worsened outcome in terms of time to a subsequent recurrence. The idea that prophylaxis, if not continued for long enough, may actually worsen the outcome of the patients receiving it is crucially important because it helps to explain why naturalistic

S.22 Psychopharmacology of bipolar disorder studies fail to show a benefit for lithium over the first 2 years of its use (Mander and Markar, 1989). For times beyond 2 years there appear to be appreciable benefits from lithium use which bears out anecdotal evidence from ordinary practice. The additional complication of lithium withdrawal which has been highlighted by Post et al. (1992) is that lithium withdrawal after years of stability may result in subsequent lithium refractoriness and poor outcome. The evidence for this remains anecdotal but appears to be real enough. The length of follow up required to establish true refractoriness and the need to systematise the approach to treatment limits the value of these observations but they are sufficiently disturbing to be taken seriously. It should be added that discontinuation is usually initiated by patients rather than doctors. The issue becomes one of how to ensure compliance and real understanding of the need for long term treatment with lithium. Neurotoxicity has always been understood to be a consequence of lithium ingestion to high plasma levels as, for example, in overdoses. The symptoms are mostly neurological and are largely reversible with cessation of therapy. What perhaps has not been appreciated is the potential for lithium toxicity at what would normally be regarded as normal lithium levels and the severity of neurotoxic damage that may result from lithium treatment in the worse cases. The clinical features are similar to the nenroleptic malignant syndrome presentation. There appears to be a particular risk if therapy is continued regardless of symptoms. The most common severe pathology is cerebellar damage and the risk is greatest in people with pre-existing organic disease, an inherited difference in rate of lithium transport into cells and perhaps the concurrent use of other drugs (particularly the phenothiazines). The issue of neurotoxicity has arisen at a time when concerns about renal damage have to some extent been allayed although the need for continuous monitoring of both plasma levels of lithium and renal function remain as a responsibility for the doctor and a potential source of problems if guidelines are not adhered to. The final challenge comes to lithium with the finding that anticonvulsant drugs appear to be as effective under acute and perhaps under prophylactic conditions. The best evidence is for valproate under acute treatment when the suggestion is that there is equal efficacy in bipolar 1 disorder and perhaps on follow up a reduced risk of depressive illness in bipolar patients treated with valproate as compared with lithium. The question of prophylaxis remains to be established by a really convincing clinical trial but anecdotal evidence proves the efficacy of valproate for longer term treatment. The appearance of newer anticonvulsants such as lamotrigine which has a more favourable side effect profile in epilepsy opens the possibility of further progress. In addition it would be interesting to understand better what the basis of the pharmacological action of lamotrigine proves to be since its spectrum of action seems to be simpler than valproate and carbamazepine, and better understood. Efforts to develop more effective anti-manic or mood stabilising drugs could result from such understanding. It would be too soon to start writing an epitaph for lithium and its use in the treatment of bipolar disorder. It remains too useful a drug to be written off in that way. However the challenge in future is to treat the 30% of patients who fall to respond to lithium more effectively and to ensure that the consequence of poor compliance are minimised by those who might respond but will not take it regularly. It is a relatively fortunate group who are both responsive to lithium and have the motivation and understanding that allows them to take it regularly under conditions of safe and effective monitoring.

References [1] Dickson, W.E. & Kendell, R.E. (1986) Does maintenance lithium therapy prevent recurrences of mania under ordinary clinical conditions? Psychological Medicine, 16, 521-530. [2] Mander, A.J. (1986) Is there a lithium withdrawal syndrome? British Journal of Psychiatry, 149, 498-501. [3] Markar, H.R. & Mander, A.J. (1989) Efficacy of lithium prophylaxis in clinical practice. British Journal of Psychiatry, 155,496-500 [4] Post, R.M., Leverich, G.S., Altshuler, L. et al (1992) Lithium-discontinuation-induced refractoriness: preliminary observations. American Journal of Psychiatry, 149-1727-1729 [5] Suppes, T., Baldessarini, R.J. Faedda, G.L. et al (1991) Risk of recurrence following discontinuation of lithium treatment in bipolar disorder. Archives of General Psychiatry, 48, 1082-1088

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[6] Goodwin, G.M. (1994) Recurrence of mania after lithium withdrawal. British Journal of Psychiatry, 164, 149-152

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Long-term prophylactic treatment priorities in bipolar disorder

C.L. Bowden. The University of Texas Health Science Center at San Antonio, Department of Psychiatry, San Antonio, Texas, USA Maintenance treatment of bipolar disorder is for most patients the most crucial component of treatment for overall degree of recovery and function. It is during maintenance treatment that issues of compliance, long-term adverse effects, subtle factors that may destabilize the patient's mood stability and both supportive and destructive relationships influence the overall quality of response. Knowledge of illness course patterns of a specific patient can optimize opportunities for early intervention. Whereas studies of a quarter century ago yielded highly successful results with lithium based maintenance therapy, studies of the past decade, mostly naturalistic in format, have yielded much more limited evidence for lithium's effectiveness. Over a 4 year follow-up period after a manic episode, only 28% of patients studied by Tohen et al did not suffer a relapse. There were no statistically significant differences in outcome measures between those taking medications, principally lithium, and those not receiving medications. Furthermore, maintenance therapy outcomes were significantly worse among bipolar than unipolar depressed patients in the large study by Harrow et al. These and similar data by other groups, including Vestergaard et al, have prompted productive investigations along three lines. Inquiry into predictors of an unfavorable outcome has yielded relatively consistent and clinically useful results. Number of previous manic and depressive episodes, psychotic features during an index manic episode, male gender, substance abuse and previous hospitalizations appear associated with unfavorable outcomes even with treatment. A second line of inquiry has been into methodolo~,dcal issues that might account for some of the variant results across studies. Maintenance studies of bipolar disorder are inherently complex, since indices of outcome include a variety of episode types, e.g., manic, mixed, depressed, hypomanic; as well as important but differing parameters such as time to relapse, functional status, percent of time well, and average symptomatology. Additionally, although randomized prospective studies employing placebo treatment groups are critically impotl:ant components of research programs on mood stabilizing drugs, such studies tend to enroll a somewhat less severely ill group of patients, contributing to difficulties in comparing results across studies. Less severely ill patients are less likely to yield drug-placebo differences in outcome than are more severely ill patients. Questions of use of concurrent medications for secondary symptoms such as psychoses, insomnia, mad breakthrough depression further complicate both the design and interpretation of maintenance studies. In the aggregate, recognition of these several factors has contributed both to more sophisticated study designs, and fairer, less confounded interpretation of study findings. The third major development has been the initiation of a series of well-conceived prospective randomized drug trials in maintenance therapy of bipolar disorder. Some of these are in progress, but several have been recently completed. Results of these studies will Ice presented and compared, with implications for clinical treatment strategies emphasized. In particular, results from a one year prospective, double blind, placebo controlled maintenance study, utilizing primarily divalproex or lithium for mood stabilization, will be presented. This study of over 300 patients presenting with a manic episode found the divalproex form of valproate better tolerated than lithium, consistent with the acute mania study of Bowden et al and the randomized maintenance study of Lambert and Deneuve. Patients treated with divalproex had fewer relapses into mania or depression than patients treated with either lithium or placebo. The duration that patients remained episode free was greater for divalproex treated than either lithium or placebo treated patients. Fewer manic episodes occurred in all treatment groups than had been prospectively predicted, principally as a function of low rates of relapse into new episodes among those patients enrolled with less severe illness courses prior to enrollment into the study. The study also provides clinically useful information regarding predictors of response or non-response to