Partial remission, residual symptoms, and relapse in depression.

Partial remission from depression, with residual symptoms, is an important problem in depression. This paper reviews the frequency and features of this outcome, and its association with relapse. Residual symptoms occur in many depressed patients after acute treatment. They span the typical symptoms of depression, except those characteristic of severe disorders. Other persistent abnormalities include social dysfunction, dysfunctional attitudes, hypothalamic-pituitary-adrenal axis overactivity, shortened REM sleep latency, and mood lowering after tryptophan depletion. Associations of some of these with residual symptoms are not clear. There is growing evidence for similar residual symptoms in bipolar disorder, particularly bipolar depression. The most important consequence of residual symptoms is a much-increased risk of relapse, particularly in the first year. Residual symptoms are a strong indication for vigorous and longer than usual continuation of antidepressant treatment in order to prevent relapse. There is good evidence for the use of cognitive therapy as an adjunct.

Do treated psychiatric patients become later community cases? A prospective cohort study.

BACKGROUND: There have been few attempts to link two aspects of psychiatric epidemiology, severe disorder and milder 'common' mental disorder, by ascertaining whether subjects who have received psychiatric treatment for major disorders are identified later in epidemiological community surveys. METHODS: Subjects were from a national birth cohort study and had been followed prospectively from childhood to middle age, with concurrent information on treatment from psychiatric facilities. In two successive prevalence surveys of milder disorder at 36 and 43 years, the association between earlier treatment and being a later community case was examined RESULTS: Among 102 subjects who had been treated patients up to age 35 years, 52 (51%) were identified as definite community cases (36, 35%) or subthreshold cases (16, 16%) at either one or both later points. The proportion of community subjects who were previous psychiatric patients increased systematically from community non-cases, through subthreshold cases on one or both occasions, definite cases on one occasion, to definite cases on both occasions. CONCLUSIONS: About half of subjects who have received treatment from psychiatric facilities remain with persistent symptoms such as to identify them as definite or subthreshold cases of milder common mental disorder some years later.

Predictors of drug response in depression.

Although the major classes of antidepressant drugs have been available for over 30 years, clinicians are still unable to predict accurately the response of their depressed patients to medication. This article reviews both clinical and biologic predictors of treatment response and makes recommendations for future studies. The tricyclic antidepressants remain the drugs of choice in major depressive disorders. Lithium has a place in bipolar depressions. Monoamine oxidase inhibitors have a role in depressions accompanied by marked anxiety and/or panic symptoms, in patients who have previously responded to them, and as a second-choice treatment in those depressed patients who have not responded to tricyclic antidepressants. Electroconvulsive therapy or additional antipsychotic drugs are frequently necessary in very severe and delusional depressions. Biologic predictors of response, despite some interesting leads that may in the long term be of considerable importance, are not yet sufficiently established to be of routine clinical usefulness, although either dexamethasone nonsuppression or a shortened rapid eye movement latency may identify depressed patients who require biologic treatment.

Suicide attempts and recent life events. A controlled comparison.

Life events experienced in the six months before a suicide attempt were compared with events for two matched control groups. Suicide attempters reported four times as many events as were reported by subjects from the general population and 11/2 times as many as were reported by depressed patients prior to depressive onset. A substantial peaking of events occurred in the month before the attempt. The excess over general population controls spanned most types of event. That over depressive onset was more selective, and it involved events with threatening implications, including undesirable events, those rated as stressful, and those outside the respondent's control. Unlike depression, suicide attempts were preceded equally by entrances and exits in the social field. Overall, the findings indicate a strong and immediate relationship between suicide attempts and life events.

Response to phenelzine and amitriptyline in subtypes of outpatient depression.

Outpatients with depression and mixed anxiety-depression were treated for six weeks with phenelzine sulfate, amitriptyline hydrochloride, or placebo in a controlled trial. Both active drugs were superior to placebo and were closely comparable in efficacy. Interactions were examined between drug response and classifications based on three different usages of the term atypical depression: additional anxiety or phobic symptoms, atypical functional shift, and nonendogenous depression. Some additional related classifications were also included. There was a tendency for phenelzine to have stronger effects in patients with additional anxiety and without evidence of chronic characterological depression. However, interactions were relatively few. These findings suggest that the two classes of antidepressant affect similar clinical subgroups within the outpatient depressive spectrum, with only relatively weak differences.

Incidence of dementia in a population older than 75 years in the United Kingdom.

BACKGROUND: Incidence studies have been relatively neglected in psychiatric epidemiology. They are particularly important for dementia, since prevalence rates are affected by length of survival, which itself falls with increasing age and presence of dementia. METHODS: Two-wave community study of 1195 elderly subjects aged older than 75 years, restudied 2.4 years after a community prevalence study. A two-stage method was used, comprising the Mini-Mental State Examination followed in a stratified sample by the Cambridge Examination for Mental Disorders of the Elderly (CAM-DEX) interview. Incidence rates were based on person-years at risk. RESULTS: Annual incidence rates for dementia were 2.3% for subjects initially aged 75 to 79 years, 4.6% for ages 80 to 84 years, and 8.5% for ages 85 to 89 years, approximately doubling every 5 years. Rates did not differ significantly by sex, educational level, or social class. Twice as many additional individuals received a diagnosis of minimal dementia not reaching case threshold. CONCLUSIONS: The findings show high rates of new onset dementia, increasing markedly with age, and suggest rapid acceleration of one or more processes that is common in advanced age.

Prevention of relapse in residual depression by cognitive therapy: a controlled trial.

BACKGROUND: Previous studies indicate that depressed patients with partial remission and residual symptoms following antidepressant treatment are common and have high rates of relapse. There is evidence that cognitive therapy may reduce relapse rates in depression. METHODS: One hundred fifty-eight patients with recent major depression, partially remitted with antidepressant treatment (mean daily doses equivalent to 185 mg of amitriptyline or 33 mg of fluoxetine) but with residual symptoms of 2 to 18 months' duration, were included in a controlled trial. Subjects were randomized to receive clinical management alone or clinical management plus cognitive therapy for 16 sessions during 20 weeks, with 2 subsequent booster sessions. Subjects were assessed regularly throughout the 20 weeks' treatment and for a further year. They received continuation and maintenance antidepressants at the same dose throughout. RESULTS: Cognitive therapy reduced relapse rates for acute major depression and persistent severe residual symptoms, in both intention to treat and treated per protocol samples. The cumulative relapse rate at 68 weeks was reduced significantly, from 47% in the clinical management control group to 29% with cognitive therapy (hazard ratio 0.54; 95% confidence interval, 0.32-0.93; intention to treat analysis). Cognitive therapy also increased full remission rates at 20 weeks but did not significantly improve symptom ratings. CONCLUSION: In this difficult-to-treat group of patients with residual depression who showed only partial response despite antidepressant treatment, cognitive therapy produced worthwhile benefit.

Altered salivary dehydroepiandrosterone levels in major depression in adults.

BACKGROUND: The authors sought to examine whether levels of dehydroepiandrosterone are abnormal in depression. METHODS: Three groups of subjects aged 20-64 were studied: 44 major depressives, 35 subjects with partially or completely remitted depression, matched as far as possible for age and drug treatment, and 41 normal control subjects. Dehydroepiandrosterone and cortisol in saliva were determined from specimens taken at 8:00 AM and 8:00 PM on 4 days. RESULTS: The mean age of the three groups did not differ. Dehydroepiandrosterone was lowered at 8:00 AM and 8:00 PM compared with control subjects. Values for the remitted group were intermediate. Dehydroepiandrosterone levels at 8:00 AM correlated negatively with severity of depression and were not related to drug treatment or smoking, but decreased with age (as expected). Cortisol was elevated in depression in the evening. The molar cortisol/dehydroepiandrosterone ratio also differentiated those with depression from the control group. CONCLUSIONS: Lowered dehydroepiandrosterone levels are an additional state abnormality in adult depression. Adrenal steroid changes are thus not limited to cortisol. Because dehydroepiandrosterone may antagonize some effects of cortisol and may have mood improving properties, these findings may have significant implications for the pathophysiology of depression.

Quantitative analysis of tau protein in paired helical filament preparations: implications for the role of tau protein phosphorylation in PHF assembly in Alzheimer's disease.

In Alzheimer's disease, there is a major redistribution of the tau protein pool from soluble to PHF-bound forms. PHF-bound tau can be distinguished from normal tau by acid reversible occlusion of a generic tau epitope in the tandem repeat region and characteristic sedimentation in the if-II protocol developed in this laboratory. We show that 85% of tau bound in the PHF-like configuration can be recovered in the if-II PHF-fraction. Less than 1% of this material was phosphorylated at the mAb AT8 site in aged clinical controls or in cases with minimal or mild dementia. Of tau phosphorylated at the mAb AT8 site, only 12% was found to co-sediment with PHFs. These low levels could not be explained by postmortem dephosphorylation. As more than 95% of PHF-tau is not phosphorylated, even at early stages of pathology, it is misleading to use the terms "PHF-tau" and "phosphorylated tau" as though they were synonymous, particularly as this implies a pathogenetic role which phosphorylation need not have.

Examination of phosphorylated tau protein as a PHF-precursor at early stage Alzheimer's disease.

Hyperphosphorylated tau protein which can be isolated on the basis of insolubility in 1% sarkosyl (A68-tau fraction) is thought to represent a precursor pool for PHF assembly, associated histologically with neuritic pathology, which feeds into a more resistant tangle-associated PHF pool via cross-linking and proteolysis. We examined these predictions at the earliest detectable stages of neurofibrillary pathology. We report that there is no evidence that neuritic pathology represents an early pathologic stage, no evidence of an association between neuritic pathology and phosphorylated tau, no evidence of selective accumulation of phosphorylated tau at early stages of pathology, and no evidence for a precursor/product relationship between phosphorylated tau and PHFs during progression of pathology. We conclude that altered phosphorylation is a secondary process affecting 5% of PHFs and does not explain PHF assembly in Alzheimer's disease.

The Defeat Depression Campaign: psychiatry in the public arena.

OBJECTIVE: The adequate recognition and treatment of depression are inhibited by negative public attitudes and gaps in professional expertise. This paper describes the activities and efforts of the Defeat Depression Campaign, a joint activity of the Royal College of Psychiatrists and the Royal College of General Practitioners, in the United Kingdom. METHOD: A 5-year campaign was undertaken from 1992 to 1996, aimed at enhancing public awareness and attitudes and providing professional education. RESULTS: An informational media campaign directed toward the general public was successfully undertaken. Leaflets, books, and audiotapes were also prepared and distributed to the public. Multiprofessional conferences on specific aspects of depression were organized. An extensive program of general practice education included consensus conferences and statements, recognition and management guidelines, training videotapes, and other publications. Public attitudes were found to be relatively favorable, except attitudes toward antidepressants, which were viewed as addictive. A general consequence of the campaign was the development of much additional public material and professional education not directly originating from the campaign. Aspects of the campaign are being evaluated, including public attitude change, impact of educational materials on general practitioners, and prescription of antidepressants. CONCLUSIONS: A campaign of this kind serves a useful function in enhancing public education and awareness and improving professional recognition and management of depression.

Population norms for the MMSE in the very old: estimates based on longitudinal data. Mini-Mental State Examination.

OBJECTIVE: To report the percentile distribution of Mini-Mental State Examination (MMSE) scores in older people by age, sex, and education level, estimated from longitudinal data, after correcting for loss due to dropout. METHODS: The Cambridge City over 75 Cohort is a population-based study of a cohort of 2106 subjects age 75 years and older at study entry followed up over 9 years. At each of the four waves, cognitive function was assessed using MMSE. Based on these data, the relationship between age and MMSE score was modeled. Percentile distributions by age, sex, and education level were provided using inverse probability weighting to correct for dropouts. RESULTS: Performance on MMSE was related to age in men and women. In women, at age 75, MMSE score ranged from 21 (10th percentile) to 29 (90th percentile). At age 95, the range was 10 (10th percentile) to 27 (90th percentile). The upper end of MMSE distribution was slightly modified with age, whereas the lower end of the distribution was very sensitive to age effect. A similar pattern was observed in both sexes. CONCLUSION: These findings provide norms for MMSE scores in subjects age 75 years and older from longitudinal population-based data. Such norms can be used as reference values to determine where an individual's score lies in relation to his or her age, sex, and education level.

Platelet [3H]imipramine and alpha 2-adrenoceptor binding in normal subjects during desipramine administration and withdrawal.

The effect of desipramine 150 mg daily on platelet [3H]imipramine and alpha 2-adrenoceptor binding sites was studied over a 6-week period and for 6 weeks after withdrawal. Modest (10%) increases in [3H]imipramine binding site densities during treatment were noted with a decrease between 1 and 4 weeks after withdrawal. No effect was found on alpha 2-adrenoceptors. Time of day appeared to have some effect on the results found. None of the [3H]imipramine binding site effects of desipramine, on treatment or following withdrawal, was comparable in magnitude to trait differences that were also found between subjects.

Analysis of the apo E/apo C-I, angiotensin converting enzyme and methylenetetrahydrofolate reductase genes as candidates affecting human longevity.

Genetic factors are likely to affect human survival, since twin studies have shown greater concordance for age of death in monozygotic compared to dizygotic twins. Coronary artery disease is an important contributor to premature mortality in the UK. Accordingly, we have chosen genes associated with cardiovascular risk, apo E/apo C-I, angiotensin converting enzyme (ACE) and methylenetetrahydrofolate reductase (MTHFR), as candidates which may affect longevity/survival into old age. An association study was performed by comparing allele and genotype frequencies at polymorphic loci associated with these genes in 182 women and 100 men aged 84 years and older with 100 boys and 100 girls younger than 17 years. MTHFR allele and genotype frequencies were similar in the elderly and young populations. Apo C-I allele and genotype frequencies were significantly different in the elderly women compared to the younger sample (P < 0.05). No difference was observed in the elderly men. At the neighbouring apo E gene, we only observed a difference between genotypes in the elderly women and the young sample; however, this did not retain significance when the genotype frequencies of the young sample were adjusted to values expected from the allele frequencies on the basis of Hardy-Weinberg equilibrium and compared to observed genotypes in elderly men and women. In contrast to previous studies, apo E2 was not overrepresented in the elderly men or women. Thus, the proposition that apo E2, E3 and E4 protein isoforms are themselves functionally associated with increasing risks for early death, may be too simplistic. The I/I ACE was depleted in the elderly males but not the elderly females. Furthermore, significant differences were observed between ACE genotypes in elderly men and elderly women. These data suggest that the penetrance of loci which influence survival may vary according to sex. The depletion of the ACE I/I genotype in elderly men is generally consistent with a previous study which found decreased frequencies of the I allele in French centenarians compared to younger controls. However, these results are apparently paradoxical, since others have suggested that the I allele is associated with increased cardiovascular risk. Clarification of the overall effect of a genotype on survival will be vital if therapies are to be considered which target specific genetic variants.

Analysis of the monoamine oxidase A (MAOA) gene in bipolar affective disorder by association studies, meta-analyses, and sequencing of the promoter.

Monoamine oxidases catalyse the oxidative degradation of biogenic amines including neurotransmitters such as noradrenaline, dopamine, and 5-hydroxytryptamine (5-HT). Three groups have reported positive associations of the monoamine oxidase A (MAOA) gene with bipolar affective disorder although other studies have been negative. In an extension of a previous study [Rubinsztein et al., 1996: Human Molec Genet 5:779-782] we report association studies of MAOA polymorphic markers and affective disorders. The polymorphisms comprised a CA-repeat microsatellite in intron 2 and a Fnu4HI G/T silent polymorphism at position 941 of the cDNA sequence. No significant differences were found when the control allele frequencies were compared with those in bipolar, unipolar, or combined bipolar + unipolar groups. Meta-analyses were then performed to include the data of all published studies using the MAOA microsatellite and Fnu4HI polymorphisms. Separate meta-analyses were performed for Caucasian and Japanese studies, as allele frequencies of the microsatellite in these populations were markedly different. Associations of bipolar affective disorder in pooled male and female groups were found with the MAOA microsatellite in both the Caucasian (P < 0.02) and the Japanese (P < 0.02) meta-analyses. In view of these positive associations, and as previous results have shown that coding variants do not account for the normal population variation in MAOA activity, over 1,300 bp of the promoter were sequenced in 22 bipolar cases and 1 control. A novel polymorphic promoter variable number of tandem repeats (VNTR) located approximately 1,200 bp upstream from the translation start site was demonstrated. However, there was no association of this promoter VNTR with affective disorder. These results suggest that there may be functional variants in other regions of the MAOA gene or neighbouring genes that affect bipolar affective disorder risk.

No association of the tryptophan hydroxylase gene with bipolar affective disorder, unipolar affective disorder, or suicidal behaviour in major affective disorder.

Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the synthesis of 5-hydroxytryptamine (5-HT). An association study in bipolar affective disorder I or unipolar major affective disorder was performed by using a Bfa I restriction site polymorphism within intron 7 of the tryptophan hydroxylase gene. A total of 118 bipolar, 125 unipolar, and 437 control subjects were used in the study (1:3.7 bipolar:control, 1:3.5 unipolar:control). There were no significant differences in TPH allele or genotype frequencies between the affective disorder and control groups. In addition, bipolar and/or unipolar subjects with or without a history of suicide attempts were compared for the TPH polymorphism. No significant differences were found between suicidal and non-suicidal groups in major affective disorder, in contrast to a previous study suggesting an association of this polymorphism with a history of suicide attempts among alcoholic violent offenders.

No association of an insertion/deletion polymorphism in the angiotensin I converting enzyme gene with bipolar or unipolar affective disorders.

A recent Japanese study on the angiotensin I converting enzyme gene (ACE) insertion/deletion polymorphism reported that both the D allele (P < 0.02) and the DD genotype (P < 0.002) were significantly more frequent in affective disorder cases than in controls [Arinami et al., 1996: Biol Psychiatry 40:1122-1127]. A replication study was performed by using 157 bipolar I affective disorder cases, 169 major depressive disorder cases, and 313 controls. No significant association with this polymorphism was found in either disorder or in a combined affective disorder group. These results do not support the ACE gene having a major role in the etiology of either bipolar or unipolar affective disorders. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:733-735, 2000.

Analysis of alpha-1 antichymotrypsin, presenilin-1, angiotensin-converting enzyme, and methylenetetrahydrofolate reductase loci as candidates for dementia.

The genetic factors which predispose individuals to dementia in old age have not been fully defined. Although the apolipoprotein E4 allele accounts for a proportion of the genetic risk for late-onset Alzheimer disease (AD), it is neither necessary nor sufficient to cause this disease. Recent suggestions that other loci are involved in dementia risk have been supported by findings of associations of genotypes at the alpha-1 antichymotrypsin (ACT) and presenilin-1 (PS-1) loci with AD. We investigated these loci in two community-based aged Cambridgeshire populations: the rural Ely population (cohort 1) comprised 60 pairs of demented and nondemented elderly individuals, with a mean age of 84.2 years; and the Cambridge city population (cohort 2) comprised 81 pairs all over age 84, with a mean age of 87.3 years. Since vascular risk factors are likely to impact on dementia risk, we also examined the angiotensin-converting enzyme (ACE) and methylenetetrahydrofolate reductase (MTHFR) genes as candidates. ACE, ACT, PS-1, and MTHFR genotype and allele frequencies were not significantly different in cases and matched controls. These data support the doubts which have been raised about the involvement of the PS-1 and ACT polymorphisms in late-onset dementia.

Genetic associations with clinical characteristics in bipolar affective disorder and recurrent unipolar depressive disorder.

Genetic factors may be associated with disease subtype as well as susceptibility. We have therefore typed polymorphisms at the serotonin transporter, dopamine receptor, tryptophan hydroxylase, tyrosine hydoxylase, and monoamine oxidase A (MAOA) loci in 139 unipolar and 131 bipolar patients and investigated associations with gender, number of episodes, age of onset, history of psychotic symptoms, history of suicidal behavior, and history of substance abuse. In bipolar subjects, the promoter variable number tandem repeat (VNTR) allele 132 of MAOA was associated with history of suicide attempts, P = 0.029, particularly in females, P = 0.006. The Fnu4HI allele 1 of MAOA was also associated with history of suicide attempts in females, P = 0.0162. The serotonin transporter promoter allele 2 was associated with increasing number of manic episodes, P = 0.02, and history of psychotic symptoms, P = 0.0243. One significant association was found in the unipolar group: dopamine D2 receptor promoter allele 2 with history of psychotic symptoms, P = 0. 0165. We have tested multiple loci for a variety of different clinical variables and performed 228 tests of significance in total. It is possible that these preliminary findings are type 1 errors, because one would expect 11 of the 228 tests to reach a nominal significance level of P < 0.05 by chance alone if all the tests were independent. The associations with the MAOA and serotonin transporter loci are consistent with previous data suggesting associations with susceptibility to bipolar affective disorder. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:36-42, 2000