1168 AMERICA SALUTES LITHIUM ALTHOUGH J. Cade reported the beneficial effects of lithium in acute mania as long ago as 1949, it took another 20 years before the drug was approved for use in the United States. In the past decade, however, lithium has had a profound impact not only on neurobiological theory and research but also on psychiatric practice. In spite of niggling worries about nephrotoxicity,’ this is a good moment to look at the value of lithium in treatment; and the Archives of General Psychiatry has devoted a special issue to the subject.2 A. Zis and F. Goodwin begin by reviewing the major clinical trials of lithium in acute mania. They point to the agreement between uncontrolled and double-blind studies that lithium induces improvement or remission in over 70% of cases, and is at least as effective as chlorpromazine for all manic symptoms except psychomotor overactivity. Their message is that lithium is the treatment of choice for all but highly overactive or atypical manics. There is similar agreement over lithium’s value in the prophylaxis of bipolar affective disorder (classical manicdepressive illness). R. Prien reviews the conclusive evidence from seven controlled trials that lithium is more effective than placebo in reducing the occurrence of further manic and depressive episodes. Lithium’s reputation as a treatment for depression is supported also by J. Mendels and his colleagues, who point to evidence of antidepressant action in nine of twelve controlled studies. The antidepressant effect seems greater in bipolar than in unipolar depressives, but even in bipolar patients it is not strong enough to make lithium a first choice
antidepressant. It is in relation
-
efficacy of lithium in the depression that dissent to M. one of the pioneers of lithSchou, begins appear. ium research, asserts that in prevention of recurrent unipolar depression lithium and the tricyclic antidepressants "are equally good or lithium is somewhat better". However, this article is preceeded by one in which Prien, in company with the Food and Drug Administration and the American Psychiatric Association, questions the evidence of a prophylactic action in unipolar depression. In the past, however, Schou has been more often right to
the
prophylaxis of ordinary unipolar
about lithium than has either of these two august bodies. Schou also discusses the efficacy of lithium in thirty conditions apart from affective disorder. Placebo-controlled studies have not confirmed enthusiastic claims of improvement in premenstrual tension and in obsessivecompulsive neurosis. But lithium does seem to lessen aggressive behaviour and has been used with benefit in antisocial prisoners and in mentally retarded patients prone to self-mutilation and temper tantrums. Some reports have suggested that it improves the outlook in alcoholism, but this may be through an effect on coexistent depression rather than by blocking the desired central effects of alcohol. So the picture which emerges is that lithium is highly effective for mania, and also has antidepressant properties. As a prophylactic it is most effective against recurrent episodes of mania in bipolar illness, followed by bipolar depression and then unipolar 1. Editorial. Lithium and the kidney: grounds for cautious optimism. Lancet 1979; ii: 1056-57. 2. Goodwin F, ed. The lithium ion. Arch Gen Psychiatry 1979; 36: 833-909.
depression. Research into its value in aggression and alcoholism point to areas where lithium may yet be of further practical use, but more importantly they support the notion that it may be symptom-specific rather than disease-specific. Which patients with affective disorder should be put on long-term lithium? Some psychiatrists start the treatment in patients who have had only a few episodes, or perhaps even a single episode, of affective illness. B. Carroll states "At this stage, a clinical trial of lithium treatment is still the only way to determine who will respond to the drug." However, lithium is not a completely innocuous form of therapy, and a therapeutic trial lasting 1 or 2 years is not a casual undertaking. Carroll is correct in stating that the search for pharmacokinetic or biochemical-functional predictors has not been rewarding. Nevertheless, a comprehensive review by Petursson3 of the published work indicates that certain clinical and genetic features are associated with a good outcome. Most importantly, the more closely a patient fits the
bipolar stereotype--episodic euphoric-grandiose to retarded-depressive-the better the chance of a good response to lithium. There are further positive correlations between lithium response and a cyclothymic premorbid personality and a pyknic body build, and a family history of bipolar illness. Non-responders tend to be chronically anxious and obsessional and to have depressive and withdrawn personalities; a history of schizophrenia or schizoaffective symptoms generally means lower responsiveness to lithium. Four or more episodes of affective disorder a year in the 2-3 years before lithium predicts a poor response, while an absence of affective episodes for 6-12 months after starting lithium heralds success. Decisions about lithium prophylaxis should be influenced by all potentially predictive indicators, by the seriousness of the condition, and by the risks and benefits of alternative treatments (such as neuroleptics in some schizoaffective disorders and tricyclic antidepressants in relapsing unipolar depression). The clinician’s task would be easier if we had a comprehensive statistical analysis of the symptoms and background characteristics in a series of lithium-responders. A longitudinal study would provide a measure of the importance of discriminant items which could then be validated in other groups.
INTRAVENOUS IMMUNOGLOBULIN HUMAN immunoglobulin preparations, consisting mostly of IgG, are being used to treat or prevent an increasing number of infections, including tetanus, hepatitis B, herpes zoster, vaccinia, and mumps. The great majority of immunoglobulin injections cause no ill effects-which is just as well, since the evidence for benefit is often circumstantial. Paradoxically, it is patients with primary antibody deficiency who are most likely to react to injections of immunoglobulin, even though their capacity for specific allergic responses may be severely limited. The reactions generally consist of back and limb pain, tachycardia, rigors, and in severe cases shock. They usually start within 30 minutes of the injection 3. Petursson H. Prediction of lithium response. 226-241.
Compr Psychiatry 1979; 20:
1169
and they were seen in 32 of the 175 patients treated in the Medical Research Council trial. Reactions are rare in boys with congenital agammaglobulinaemia and in pa-
secondary immunodeficiency. They happen other antibody-deficient patients and are thought to result from complement activation by IgG aggregates in the injection, rather than from an allergic response. Conventionally prepared IgG is suitable only for intramuscular injection; it can cause severe reactions when given intravenously. But, large intramuscular injections are painful, so the amount of immunoglobulin which can be given by this route is limited. This is unfortunate because the M.R.C./triaP showed that patients receiving 50 mg/kg/week of IgG had significantly tients with
sporadically in
fewer infections than those on the standard dose of 25 mg/kg/week. The smaller dose was recommended for routine prophylaxis in antibody deficiency partly out of consideration of the volume of the injection. Nolte and co-workers3 in Oregon have now shown that antibodydeficient patients given 150 mg/kg monthly had significantly fewer infections than others given about 50 mg/kg/month (the lower dose being substantially less than that routinely used in the U.K.). The higher dose was made possible through the use of a new IgG preparation, suitable for intravenous injection, in which immunoglobulin aggregation is prevented by mild reduction and alkylation. This is a considerable advance on the enzyme-digested IgG preparations, which lack the Fc region of the molecule and so have subnormal opsonising activity and a half-life in the circulation of only 5-6 days. The new intravenous preparation has a halflife of about 20 days and retains over 80% of the original antibody activity. One-third of the patients with primary antibody deficiency had transient nausea, fever, flushing, and muscle cramps after the infusions while those with secondary immunodeficiency were spared these effects. No patients had the severe reactions which sometimes follow intramuscular injections of the standard IgG. Ochs4 found that total hmmolytic complement and C3 levels fell slightly after intravenous IgG infusions and that the transient minor reactions were lessened or abolished by 600 mg of aspirin taken 30 minutes before the infusion. Ochs and co-workers will soon be reporting a two-year blind cross-over study comparing intravenous with intramuscular treatment. Meanwhile other smaller-scale studies are confirming the view that preparations of IgG suitable for intravenous use are effective and highly acceptable to patients; these include pH 4 treated material tested by Barandunsand S-sulphonated IgG used by Yamanaka et al.6 The reasons why S-sulphonation is so effective are not clear but the treated molecules reconvert to their native form within 24 hours of administration and they
1. Soothill
JF. Reactions to immunoglobulin. In: Hypogammaglobulinæmia in the United Kingdom. MRC Spec Rep Ser No. 310, 1971. LE, Mollison PL. Conclusions. In: Hypogammaglobulinæmia in the
2. Hill
United Kingdom. MRC Spec Rep Ser No. 310, 1971. 3. Nolte MT, Pirofsky B, Gerritz GA, Golding B. Intravenous immunoglobulin therapy for antibody deficiency. Clin Exp Immunol 1979; 36: 237-43. 4. Ochs HD. Prophylactic treatment of immunodeficiency syndromes with intravenous gammaglobulin. Vox Sang 1979; 37: 126-28. 5. Barandun S. Use of intravenous gammaglobulin in the treatment of severe bacterial infection. Vox Sang 1979; 37: 117-19. 6. Yamanaka T, Abo W, Chiba S, et al. Clinical effect and metabolism of s-sulphonated immunoglobulin in 7 patients with congenital humoral immunodeficiency. Vox Sang 1979; 37: 14-20.
in the circulation with a half-life of 21 days. No reactions have been reported in the small number of patients treated. Commercial exploration of intravenous IgG preparations is doubtless undertaken in the hope that they may have wider clinical application than mere immuno-
persist
deficiency-for instance, life-threatening infections, particularly with septicaEmia, and sepsis of the newborn. Clinical trials in these areas are very difficult to organise very informative results are yet to hand. On evidence there is ’a strong case for further evaluation of intravenous IgG in treatment of antibody deficiency in the U.K. Until intravenous preparations are more widely available it may be to the patient’s ultimate advantage to be generous with intramuscular IgG, despite the added pain of injection.
and
no
existing
VARIABLE RESPONSE TO GLUTEN CHALLENGE MOST paediatricians now accept that final diagnosis of cceliac disease in childhood rests on healing of the smallintestinal mucosa when gluten is withdrawn followed by histological relapse after gluten challenge.’ Now Kumar and colleagues2 have used these diagnostic criteria when trying the reintroduction of gluten into the diet of teenagers and adults diagnosed as having coeliac disease and on a gluten-free regimen. The first group, 9 teenagers diagnosed in childhood, relapsed histologically a very variable time after gluten reintroduction, 5 taking more than 7 weeks, the longest 10 months. In the second group, all diagnosed after puberty, 18 of 19 relapsed within 7 weeks but 1 had a normal mucosa 2 years after return to a gluten-containing diet. This is the first reported instance in an adult of something now familiar in the paediatric world-namely, absence of relapse after two years’ gluten challenge, despite an earlier flat small-intestinal mucosa and response to a gluten-free diet.3-5 Most of these children have continued to do well,3,4 but one relapsed histologically after 63 months.5 This remarkable variation in histological response, especially in patients diagnosed in childhood, is quite unexplained. Kumar’s findings resembled the paediatric results in other respects. 7 patients had no symptoms whatever despite morphological relapse, and there was no correlation with duration of the gluten-free diet. They also substantiate the. observation3 that a normal mucosa after 3 months of gluten challenge does not exclude cceliac disease, as was suggested by some workers.6 Whether the same applies in most patients after two years of gluten remains to be seen.
1. Meeuwise GW. Diagnostic criteria in cæliac disease. Acta Pædiat Scand 1970; 59: 461-63. 2. Kumar PJ, Donoghue DP, Stenson K, Dawson AM. Reintroduction of gluten in adults and children with treated cæliac disease. Gut 1979; 20: 743-49. 3. Walker-Smith JA, Kilby A, France NE. Reinvestigation of children previously diagnosed as cæliac disease. In: McNicholl B, McCarthy CF, Fottrell PF, eds. Perspectives in cæliac disease. Lancaster: MTP, 1978: 267. 4. Nusslé D, Bozic C, Cox J, Deleze G, Roulet M, Fete R, Megevana A. Noncæliac gluten intolerance in infancy. In: McNicholl B, McCarthy CF, Fottrell PF, eds. Perspectives in cœliac disease. Lancaster: MTP, 1978: 277. 5. McNicholl B, Egan-Mitchell B, Fottrell PF. Variability of gluten intolerance in treated childhood cæliac disease. Gut 1979; 20: 126-32. 6. Packer SM, Charlton V, Keeling JW, Risdon RA, Ogilvie D, Rowlatt RJ, Larcher VF, Harries JT. Gluten challenge in treated cœliac disease. Arch Dis Childh 1978; 53: 449-55.
antidepressant. It is in relation
-
efficacy of lithium in the depression that dissent to M. one of the pioneers of lithSchou, begins appear. ium research, asserts that in prevention of recurrent unipolar depression lithium and the tricyclic antidepressants "are equally good or lithium is somewhat better". However, this article is preceeded by one in which Prien, in company with the Food and Drug Administration and the American Psychiatric Association, questions the evidence of a prophylactic action in unipolar depression. In the past, however, Schou has been more often right to
the
prophylaxis of ordinary unipolar
about lithium than has either of these two august bodies. Schou also discusses the efficacy of lithium in thirty conditions apart from affective disorder. Placebo-controlled studies have not confirmed enthusiastic claims of improvement in premenstrual tension and in obsessivecompulsive neurosis. But lithium does seem to lessen aggressive behaviour and has been used with benefit in antisocial prisoners and in mentally retarded patients prone to self-mutilation and temper tantrums. Some reports have suggested that it improves the outlook in alcoholism, but this may be through an effect on coexistent depression rather than by blocking the desired central effects of alcohol. So the picture which emerges is that lithium is highly effective for mania, and also has antidepressant properties. As a prophylactic it is most effective against recurrent episodes of mania in bipolar illness, followed by bipolar depression and then unipolar 1. Editorial. Lithium and the kidney: grounds for cautious optimism. Lancet 1979; ii: 1056-57. 2. Goodwin F, ed. The lithium ion. Arch Gen Psychiatry 1979; 36: 833-909.
depression. Research into its value in aggression and alcoholism point to areas where lithium may yet be of further practical use, but more importantly they support the notion that it may be symptom-specific rather than disease-specific. Which patients with affective disorder should be put on long-term lithium? Some psychiatrists start the treatment in patients who have had only a few episodes, or perhaps even a single episode, of affective illness. B. Carroll states "At this stage, a clinical trial of lithium treatment is still the only way to determine who will respond to the drug." However, lithium is not a completely innocuous form of therapy, and a therapeutic trial lasting 1 or 2 years is not a casual undertaking. Carroll is correct in stating that the search for pharmacokinetic or biochemical-functional predictors has not been rewarding. Nevertheless, a comprehensive review by Petursson3 of the published work indicates that certain clinical and genetic features are associated with a good outcome. Most importantly, the more closely a patient fits the
bipolar stereotype--episodic euphoric-grandiose to retarded-depressive-the better the chance of a good response to lithium. There are further positive correlations between lithium response and a cyclothymic premorbid personality and a pyknic body build, and a family history of bipolar illness. Non-responders tend to be chronically anxious and obsessional and to have depressive and withdrawn personalities; a history of schizophrenia or schizoaffective symptoms generally means lower responsiveness to lithium. Four or more episodes of affective disorder a year in the 2-3 years before lithium predicts a poor response, while an absence of affective episodes for 6-12 months after starting lithium heralds success. Decisions about lithium prophylaxis should be influenced by all potentially predictive indicators, by the seriousness of the condition, and by the risks and benefits of alternative treatments (such as neuroleptics in some schizoaffective disorders and tricyclic antidepressants in relapsing unipolar depression). The clinician’s task would be easier if we had a comprehensive statistical analysis of the symptoms and background characteristics in a series of lithium-responders. A longitudinal study would provide a measure of the importance of discriminant items which could then be validated in other groups.
INTRAVENOUS IMMUNOGLOBULIN HUMAN immunoglobulin preparations, consisting mostly of IgG, are being used to treat or prevent an increasing number of infections, including tetanus, hepatitis B, herpes zoster, vaccinia, and mumps. The great majority of immunoglobulin injections cause no ill effects-which is just as well, since the evidence for benefit is often circumstantial. Paradoxically, it is patients with primary antibody deficiency who are most likely to react to injections of immunoglobulin, even though their capacity for specific allergic responses may be severely limited. The reactions generally consist of back and limb pain, tachycardia, rigors, and in severe cases shock. They usually start within 30 minutes of the injection 3. Petursson H. Prediction of lithium response. 226-241.
Compr Psychiatry 1979; 20:
1169
and they were seen in 32 of the 175 patients treated in the Medical Research Council trial. Reactions are rare in boys with congenital agammaglobulinaemia and in pa-
secondary immunodeficiency. They happen other antibody-deficient patients and are thought to result from complement activation by IgG aggregates in the injection, rather than from an allergic response. Conventionally prepared IgG is suitable only for intramuscular injection; it can cause severe reactions when given intravenously. But, large intramuscular injections are painful, so the amount of immunoglobulin which can be given by this route is limited. This is unfortunate because the M.R.C./triaP showed that patients receiving 50 mg/kg/week of IgG had significantly tients with
sporadically in
fewer infections than those on the standard dose of 25 mg/kg/week. The smaller dose was recommended for routine prophylaxis in antibody deficiency partly out of consideration of the volume of the injection. Nolte and co-workers3 in Oregon have now shown that antibodydeficient patients given 150 mg/kg monthly had significantly fewer infections than others given about 50 mg/kg/month (the lower dose being substantially less than that routinely used in the U.K.). The higher dose was made possible through the use of a new IgG preparation, suitable for intravenous injection, in which immunoglobulin aggregation is prevented by mild reduction and alkylation. This is a considerable advance on the enzyme-digested IgG preparations, which lack the Fc region of the molecule and so have subnormal opsonising activity and a half-life in the circulation of only 5-6 days. The new intravenous preparation has a halflife of about 20 days and retains over 80% of the original antibody activity. One-third of the patients with primary antibody deficiency had transient nausea, fever, flushing, and muscle cramps after the infusions while those with secondary immunodeficiency were spared these effects. No patients had the severe reactions which sometimes follow intramuscular injections of the standard IgG. Ochs4 found that total hmmolytic complement and C3 levels fell slightly after intravenous IgG infusions and that the transient minor reactions were lessened or abolished by 600 mg of aspirin taken 30 minutes before the infusion. Ochs and co-workers will soon be reporting a two-year blind cross-over study comparing intravenous with intramuscular treatment. Meanwhile other smaller-scale studies are confirming the view that preparations of IgG suitable for intravenous use are effective and highly acceptable to patients; these include pH 4 treated material tested by Barandunsand S-sulphonated IgG used by Yamanaka et al.6 The reasons why S-sulphonation is so effective are not clear but the treated molecules reconvert to their native form within 24 hours of administration and they
1. Soothill
JF. Reactions to immunoglobulin. In: Hypogammaglobulinæmia in the United Kingdom. MRC Spec Rep Ser No. 310, 1971. LE, Mollison PL. Conclusions. In: Hypogammaglobulinæmia in the
2. Hill
United Kingdom. MRC Spec Rep Ser No. 310, 1971. 3. Nolte MT, Pirofsky B, Gerritz GA, Golding B. Intravenous immunoglobulin therapy for antibody deficiency. Clin Exp Immunol 1979; 36: 237-43. 4. Ochs HD. Prophylactic treatment of immunodeficiency syndromes with intravenous gammaglobulin. Vox Sang 1979; 37: 126-28. 5. Barandun S. Use of intravenous gammaglobulin in the treatment of severe bacterial infection. Vox Sang 1979; 37: 117-19. 6. Yamanaka T, Abo W, Chiba S, et al. Clinical effect and metabolism of s-sulphonated immunoglobulin in 7 patients with congenital humoral immunodeficiency. Vox Sang 1979; 37: 14-20.
in the circulation with a half-life of 21 days. No reactions have been reported in the small number of patients treated. Commercial exploration of intravenous IgG preparations is doubtless undertaken in the hope that they may have wider clinical application than mere immuno-
persist
deficiency-for instance, life-threatening infections, particularly with septicaEmia, and sepsis of the newborn. Clinical trials in these areas are very difficult to organise very informative results are yet to hand. On evidence there is ’a strong case for further evaluation of intravenous IgG in treatment of antibody deficiency in the U.K. Until intravenous preparations are more widely available it may be to the patient’s ultimate advantage to be generous with intramuscular IgG, despite the added pain of injection.
and
no
existing
VARIABLE RESPONSE TO GLUTEN CHALLENGE MOST paediatricians now accept that final diagnosis of cceliac disease in childhood rests on healing of the smallintestinal mucosa when gluten is withdrawn followed by histological relapse after gluten challenge.’ Now Kumar and colleagues2 have used these diagnostic criteria when trying the reintroduction of gluten into the diet of teenagers and adults diagnosed as having coeliac disease and on a gluten-free regimen. The first group, 9 teenagers diagnosed in childhood, relapsed histologically a very variable time after gluten reintroduction, 5 taking more than 7 weeks, the longest 10 months. In the second group, all diagnosed after puberty, 18 of 19 relapsed within 7 weeks but 1 had a normal mucosa 2 years after return to a gluten-containing diet. This is the first reported instance in an adult of something now familiar in the paediatric world-namely, absence of relapse after two years’ gluten challenge, despite an earlier flat small-intestinal mucosa and response to a gluten-free diet.3-5 Most of these children have continued to do well,3,4 but one relapsed histologically after 63 months.5 This remarkable variation in histological response, especially in patients diagnosed in childhood, is quite unexplained. Kumar’s findings resembled the paediatric results in other respects. 7 patients had no symptoms whatever despite morphological relapse, and there was no correlation with duration of the gluten-free diet. They also substantiate the. observation3 that a normal mucosa after 3 months of gluten challenge does not exclude cceliac disease, as was suggested by some workers.6 Whether the same applies in most patients after two years of gluten remains to be seen.
1. Meeuwise GW. Diagnostic criteria in cæliac disease. Acta Pædiat Scand 1970; 59: 461-63. 2. Kumar PJ, Donoghue DP, Stenson K, Dawson AM. Reintroduction of gluten in adults and children with treated cæliac disease. Gut 1979; 20: 743-49. 3. Walker-Smith JA, Kilby A, France NE. Reinvestigation of children previously diagnosed as cæliac disease. In: McNicholl B, McCarthy CF, Fottrell PF, eds. Perspectives in cæliac disease. Lancaster: MTP, 1978: 267. 4. Nusslé D, Bozic C, Cox J, Deleze G, Roulet M, Fete R, Megevana A. Noncæliac gluten intolerance in infancy. In: McNicholl B, McCarthy CF, Fottrell PF, eds. Perspectives in cœliac disease. Lancaster: MTP, 1978: 277. 5. McNicholl B, Egan-Mitchell B, Fottrell PF. Variability of gluten intolerance in treated childhood cæliac disease. Gut 1979; 20: 126-32. 6. Packer SM, Charlton V, Keeling JW, Risdon RA, Ogilvie D, Rowlatt RJ, Larcher VF, Harries JT. Gluten challenge in treated cœliac disease. Arch Dis Childh 1978; 53: 449-55.
