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The relationships between dosage, plasma concentration, antidepressant response and toxicity were investigated in 24 highly selected patients with severe, refractory major depression who were prescribed amitriptyline, clompramine or dothiepin at high dosage (150–525 mg/day), usually in combination with lithium or other psychotropics. of serious adverse effects 83 per cent were encountered when tricyclic antidepressant (TCA) plasma concentrations exceeded 400 mcg/1. Therapeutic drug monitoring of high dose TCAs is useful in minimizing the risk of toxicity and in revealing poor compliance, undertreatment and pharmacokinetic interactions which can mitigate against drug efficacy. The value of carbamazepine in the management of refractory depression in the context of unipolar affective disorder is put into question.

SYNOPSISThis study describes a cohort of 23 patients undergoing stereotactic subcaudate tractotomy. Research Diagnostic Criteria indicated that 70% suffered major depressive disorder; the remainder mostly had a bipolar affective disorder. There were serial assessments pre-operatively and at 2 weeks and 6 months post-operatively using the Hamilton Rating Scale for depression, the Present State Examination (PSE), Newcastle Scale, the Beck Depression Inventory, and the Taylor Manifest Anxiety Scale. Neuropsychological assessment included tests thought to be sensitive to frontal lobe dysfunction, as well as tests of general intelligence, attention, memory, language and visuo-spatial function.Post-operatively, depression rating scale scores decreased significantly but most patients continued to exhibit a number of PSE syndromes. Depression rating scale scores were correlated with 1 year global outcome: there was no significant correlation except for the 6 month assessment when lower Hamilton scores were found to be associated with better global outcome. Correlations between the neuropsychological tests and the Hamilton and Beck depression scales at 2 weeks post-operatively suggested that an improvement in psychiatric condition was associated with greater efficiency on some tests of attention and verbal recall, as well as faster performance on a sorting task. By contrast, the changes at 6 months suggested an association between improvement in psychiatric condition and less efficient performance on certain neuropsychological tests including verbal recognition memory, attention and two tests of frontal lobe dysfunction.

BackgroundStereotactic subcaudate tractotomy (SST) is the only type of psychosurgery performed at the Geoffrey Knight Unit, London, where nearly 1300 operations have been done since 1961. Statistically reliable data are not available to prove the effectiveness of SST. A detailed statement about contemporary psychosurgery is given.MethodRelevant publications from the Unit and via Medline are discussed. The outcome figures are reviewed. The outcome is assessed at the Unit in global and clinical terms, associated with results of self-completed questionnaires.ResultsST allows 40–60% of patients to live normal or near-normal lives, perhaps with continuation of medication. A reduction in suicide rate to 1% postoperatively, from 15% in cases of uncontrolled affective disorders is seen.ConclusionAs a treatment of last resort, no controlled trial against a comparable treatment is possible. It appears reasonable to offer SST to patients with suicidal and deluded depression or with frequently swinging moods, not responding to other treatments.

The psychosurgical operation of stereotactic subcaudate tractotomy (SST) is performed for patients who have treatment resistant affective illness refractory to electroconvulsive therapy (ECT) and vigorous pharmacotherapy (Bartlett et al. 1981). The operation consists of placing ten yttrium-90 rods, 7mm long by 1 mm in diameter, in the ventroposterior quadrant of the frontal lobes. They are placed stereotactically using a Macaul frame by taking repeat anteroposterior and lateral air ventriculograms and hence calculating the siting. Some 60% of patients get well either on or off medication; the response is slow, requiring 3–12 months. Some 20 patients from the whole UK are operated on every year. There are no major adverse personality changes (Goktepe et al. 1975). This pilot study was undertaken to determine the precise siting of the lesion, the effects of the operation on the brain at various postoperative times and the optimal time intervals for magnetic resonance imaging (MRI) of the patients postoperatively.

Aspartic acid, 5-hydroxyindoleacetic acid, glutamic acid, homovanillic acid and 3-methoxy-4-hydroxyphenylethylene glycol was determined in samples of ventricular fluid from 82 subjects. Laminar distribution of the total number (Bmax value) of serotonin 1A receptors was determined on seven neurosurgical samples of neocortex. Apart from an association in a small subgroup of subjects between homovanillate concentration and corticosteroid medication, no complicating influences of treatment preceding operation were found. The content of the serotonin metabolite alone was significantly reduced in intractable depressive illness (bipolar and major depressive disorders) compared with neurological conditions subdivided into Alzheimer's disease, other dementias and other conditions. There was no other significant difference between these groups for the compounds measured. The total number of serotonin 1A receptors was highest in the superficial layers, being considerably higher than in the rat, irrespective of cortical layer. This part of the study indicated that these receptors are important for regulating activity of human corticocortical glutamatergic neurons. The results are discussed in relation to treating depression with serotonergic agents and targeting corticocortical glutamatergic neurons as well as acetylcholine in Alzheimer's disease.

Samples of ventricular CSF were taken from 52 consecutive patients admitted for psychosurgery for intractable depression. Concentrations of asparagine, aspartate, glutamine, glutamic acid, and serine were determined. Glutamate and aspartate concentrations, implicated in excitotoxic brain damage, were not affected by various types of psychotropic drug treatment. Serine, a modulator of glutamate responses, was significantly elevated in samples from subjects receiving antidepressants. These subjects responded poorly to the operation. Psychotropic drugs are unlikely to be neurotoxic. Nevertheless, antidepressants may influence excitatory neurotransmission.

The MRI T1 proton relaxation values were assessed in 14 patients with bipolar affective disorder and 10 with a unipolar disorder and a matched normal control group. The T1 values in the frontal white matter of patients significantly exceeded those of the controls. This difference was accounted for by an increase in T1 values in the frontal white matter of unipolar patients: the values for bipolar patients alone did not differ from those for controls. These preliminary findings support a hypothesis of frontal lobe dysfunction mediating pathological changes in mood.

SummaryThe growth hormone responses to clonidine (1.3 μg/kgm) and apomorphine (0.005 mg/kgm) have been measured in 8 drug free patients with endogenous depression. In these patients the growth hormone responses to clonidine were significantly smaller than to apomorphine. As these doses of clonidine and apomorphine have previously been reported to cause similar growth hormone responses in normal subjects, these findings support the hypothesis of a defect in the adrenergic but not the dopaminergic regulation of growth hormone in patients with endogenous depression.

Summary The widespread use of standard leucotomy terminated in the early 1950's with the advent of the phenothiazine group of drugs. But since then, psychosurgical techniques have been considerably refined and the indications for the newer operations are becoming increasingly precise. Knight's (1969) stereotactic tractotomy is probably the most frequently performed contemporary operation for the relief of some psychiatric illnesses, and the number of patients now referred for this treatment have justified the organization of a specific unit for the purpose. The value of such a special unit, involving close co-operation between neurosurgeon and psychiatrist is emphasized. It provides a supportive environment for patients who are sharing a highly specialized treatment, and offers opportunities for studying outcome after operation with resulting improvement in selection. It also facilitates research possibilities in general. The clinical work of the Geoffrey Knight Psychosurgical Unit, probably in its way unique, is described and questions often encountered from doctors and from patients are considered. The importance of rehabilitation after operation is stressed and some aspects of the longer term post-operative psychiatric care involved are dealt with.

A double-blind trial was carried out in 9 patients with endogenous depression to compare the effectiveness of bromocriptine (15 mg per day, 4 patients) with that of imipramine (75 mg per day, 5 patients) over a period of 10 weeks. The results of assessments using the Hamilton Rating Scale for Depression showed that both drugs produced comparable reduction in mean scores and there was no significant difference between the two treatment groups. Fewer patients han anticholinergic type side-effects on bromocriptine although some had transient nausea.

The relationship between neurotransmitter metabolite concentrations and measurements of ventricular size on CAT scans and pneumoencephalographs was investigated in 15 patients with severe affective disorder. An association was identified between reduced levels of plasma free tryptophan and ventricular enlargement and also between raised ventricular CSF levels of 5 HIAA and ventricular enlargement.

All patients with primary obsessional illnesses who underwent operation at least three years previously attended for a detailed review and a relative also came to give additional information. These 24 obsessional patients were compared to 24 patients with primary depressive illnesses, matched for sex and age, who also had psychosurgical operations at least three years before, and who also brought a close relative. Only two patients in each diagnostic group reported no improvement of any kind in the three years since operation, but more definite improvement (I and II) occurred in 67 per cent of the obsessionals and 71 per cent of the depressed patients. In this series no patient reported having become worse since operation. The backgrounds of the two groups were quite closely similar, except for a higher incidence of disturbed relationships with parents during childhood, especially the father, among the obsessionals, and there were a larger number of depressed patients reporting the death of one or other parent before the patient was 16 years old. In addition, there was evidence of more psychiatric illness among the close relatives of the obsessionals than was the case with the depressive group, but one quarter of the latter reported the loss of either a parent or sibling by suicide. However, these background factors could not be related to prognosis after operation. It was found that obsessionals who did poorly tended to have illnesses of an earlier onset (mean 22 years) compared to those who did well (33 years), and their illnesses tended to have begun suddenly. In the case of the depressed group the age of onset showed no relationship to outcome, and there was a tendency for illnesses of gradual onset to have a better prognosis. For all patients an onset in pregnancy or the puerperium was associated with a particularly good response. There was evidence to suggest that in general the presence of prominent depression improved the prognosis. Psychological tests given to the patients at the time of the review discriminated well between those of good outcome and those whose response was poor, but there was less differentiation between the two diagnostic groups.

Psychiatric patients undergoing the psychosurgical operation of stereotactic subcaudate tractotomy were infused intravenously with either saline or L-tryptophan (15 mg/kg/h). Plasma, lumbar cerebrospinal fluid (CSF), ventricular CSF and a specimen of frontal cortex were collected. The relationships of plasma concentrations of substances claimed to influence brain tryptophan concentration (total tryptophan, free tryptophan, large neutral amino acids) with the concentration of tryptophan in the cortex and CSF were investigated. Tryptophan infusion resulted in plasma tryptophan values comparable to those found after oral doses used in treating depression or insomnia, and about sixfold increases of tryptophan in the cerebral cortex. Increased brain 5-hydroxytryptamine synthesis was indicated by significant rises of CSF 5-hydroxyindoleacetic acid. The concentration of plasma free tryptophan was a better predictor than plasma total tryptophan of cortex tryptophan concentration. As all correlation coefficients of plasma versus brain or plasma versus ventricular CSF tryptophan concentrations were decreased when allowance was made for differences of concentration of large neutral amino acids, the results suggest that the role of these substances within their physiological range as inhibitors of tryptophan transport to the brain may previously have been overemphasised.

Between 1979 and 1986 the number of psychosurgical operations carried out in Britain fell from 70 to 15 procedures annually. There are a number of possible reasons for this change of which increased experience with new regimes of psychotropic medication is perhaps the most important. The new Mental Health Act (1983) which brought psychosurgery under the direct jurisdiction of the law was followed by a sudden reduction in the number of patients treated but referals are now increasing. In current psychiatric practice, classification relies largely on description of syndromes, each characterised by a set of core symptoms. Schizophrenia and affective psychoses (endogenous depression, mania and obsessional illness of late onset) are characterised by disturbances of mood, thinking and perception often so profound as to impair the patient's contact with reality. In contrast, neuroses produce symptoms which are quantitatively, rather than qualitatively different from normal experience and psychosurgery has no place in their treatment. Following the introduction of phenothiazines in the early 1950's schizophrenia ceased to be an indication for psychosurgery. For a small group of severely disabled and distressed people suffering from endogenous depressive and obsessional illnesses, when other treatments have failed or ceased to be effective, psychosurgery remains an appropriate treatment. Just over half the patients treated at the Geoffrey Knight Unit are relieved to the extent that they are either free of symptoms or such symptoms that remain do not significantly impair social function. Following operation recovery is slow and progressive and a programme of rehabilitation is usually necessary. Personality which is often severely damaged by the effects of long illness returns towards normal. Neuropsychiatric evaluation has consistently failed to demonstrate adverse cognitive effects. Evaluation and selection of patients for operation should be done by a psychiatrist and neurosurgeon working in partnership. Stereotactic techniques have made it possible to produce precisely located lesions of consistent size, virtually eliminating side effects and reducing the epileptic risk to between two and three percent. The Mental Health Act, contrary to early expectations, has allowed that psychosurgery retains a place in the treatment of a small highly selected group of patients.

The initial period of enthusiasm for the surgical treatment of certain psychiatric illnesses, has later given way to increasing rejection of this mode of therapy. But more recently there has been a reappraisal of the therapeutic possibilities of the modern refined operations, which are now receiving more objective assessment.

Seven patients suffering from severe endogenous depression who had proven resistant to lengthy trials of treatment with tricyclic and other antidepressants are described. Their successful treatment with a combination of clomipramine, L-tryptophan and lithium is discussed in the context of other strategies for the treatment of resistant depression.

Plasma, cerebrospinal fluid and brain tissue amino acid levels were measured in 14 patients with affective illness and generally confirm previous findings. There was no correlation between these values and age, sex, family history and levels of anxiety. GABA levels measured in cortex tissue were negatively correlated with depressive mood (P less than 0.05), supporting a possible involvement of GABA in depressive illness.

Summary There is a popular conviction that psychological disturbance is invariably a reaction to environmental events. This approach is associated with total rejection of the so-called ‘medical model’. However, allowance must be made for the fact that contemporary knowledge of psychiatric illness is well behind what is now known about general medicine, and current ideas about psychiatric aetiology may be emotionally determined to give satisfying concepts which are often almost impossible to refute. By tracing the progress of some hypotheses in general medicine, as they developed in the past, there are similarities with some current observations about the methods of action of physical treatments in psychiatry, treatments which have been discovered empirically. There is a widespread assumption that psychological responses relate precisely to the degree of evoking stress or the patient's personal attitudes to the stress. However, emotional responsiveness may show an intrinsic individual variation so that many patients who over-respond to stress may do so because of enhanced responsiveness rather than necessarily because psychological events have brought about a state of vulnerability. The exclusively dynamic approach to psychiatry has been perhaps unnecessarily encouraged by naming an illness ‘endogenous depression’ which could well be a primarily physical metabolic disturbance in the central nervous system but which happens to present with prominent depression, as well as other abnormalities. The emphasis on the component of depressed mood artificially delineates the illness and tends to impede consideration of its wider implications.

SummaryThe growth hormone and hypotensive responses to clonidine have been measured in six drug free severely depressed patients before, and at two weeks after, the surgical procedure of stereotactic sub-caudate tractotomy. The responses were unaltered two weeks after operation, by which time a small clinical improvement was evident. These findings are discussed in relation to central a adrenoceptor functions in depression, and the effect upon this of antidepressant treatment.

The Geoffrey Knight Psychosurgical Unit admits patients on a regular basis and thus offers special opportunities for studying severely ill psychiatric cases, all having one particular treatment under relatively controlled conditions. The opportunity has been taken to repeat various metabolic studies previously reported to be abnormal in some psychiatric illnesses. In the present investigation several measures of endocrinological activity were studied, as was plasma tryptophan, both free and bound. None of these data confirmed reports of abnormalities and neither did the values found at operation help to predict clinical outcome 1 year later, which was another possibility. Urinary catecholamines were also measured before and 2 weeks after operation. Male patients, regardless of diagnosis, showed a mean increase in adrenaline output after operation compared with the pre-operative value and this was significantly different from the females, who showed a small mean decrease. The depressed patients showed a significant reduction in noradrenaline excretion after operation compared with before operation and this trend was enhanced in those of good outcome at 1 year, the difference from those who responded poorly being significant. It could be that the ventromedial lesion that is produced alters noradrenaline metabolism or autonomic activity in depression and this possibility merits further study.

Thirty-five patients were studied by EEG with recordings taken the day before, two weeks after, and six months after psychosurgery. Most showed a characteristic frontal slow activity of varying degrees after operation with varying enhancement of background activity. The amount and spread of the frontal slow waves two weeks after operation showed a significant positive correlation with the clinical outcome one year later, which suggests a relatively objective and very early indication of the subsequent clinical response to psychosurgery.

There are now a large number of potent physical treatments available for the depressed patient. Some of these carry an appreciable morbidity, and it is no longer appropriate that the physician should choose between them either at random or according to personal preference. The concept of the endogenous depressive process as a physiological state, aetiologically distinct from depressive changes which are dependent on psychological mechanisms, is widely accepted on the Continent, but is viewed with suspicion by many workers in America and in this country. Though it is often alleged that psychiatric diagnosis is a barren exercise, patients and the relatives of patients who suffer from manic-depressive disease can sometimes distin guish with clarity. between depressive attacks which are physiological in type and depressive spells which are reactive in origin and symptomatically different. These physiological depressions may arise, proceed, and remit without regard to psychological events. The concept of manic-depressive disease as a specific illness stems from the clinical observations of Falret (1854) and Baillarger (1854). In addition to manic-depressive disease, the term " endogenous depression " is now applied to single episodes of depression which are thought to be aetiologically distinct from manic-depressive disease. Further, many authors distinguish a subgroup of single depressions which are said to occur characteristically at the involutional period (involutional depression). These variants of endogenous depression are thought to be illnesses throughout which the patient retains the potentiality of complete remission. These illnesses occur typically in individuals with certain constitutional characteristics and are probably genetically dis tinct. Thus we are dealing with two sets of physiological and psychological phenomena : those which characterize the illnesses or attack states and differentiate patients from well people, and those which distinguish the constitutional make-up of indi viduals who are prone to these types of illness. The former phenomena should disappear with spontaneous remission or with successful treatment ; the latter are likely to persist unless the treatment produces a change in the constitution which may provide protection against future attacks. In any attempt, therefore, to seek diagnostic criteria it is important to distinguish between these two sets of physiological and psychological phenomena. One of the classic symptoms of endogenous depression is a diurnal variation in mood and symptomatology, which was, we believe, first described by Schneider (1920). In physio logical depression the depressive process is typically at its maximum in the early hours of the morning, and tends to improve during the day. In psychogenic or reactive depression it is said that each new day starts more hopefully than it finishes.

My association with the psychosurgical unit now carrying out over 80 per cent of these operations in Britain affords an unusual opportunity to assess the management of treatment-resistant affective disorders by a large number of psychiatrists from various parts of the country. The psychiatrists likely to refer patients for psychosurgery would be expected to be those more inclined to use psychotropic medication and physical treatments in general. Nonetheless, our experience is unequivocally of a widespread under-use of antidepressants. Most referral letters state that ‘… just about every antidepressant has been tried …’, but it is rare for the maximum dose of each drug used to be quoted. The letters suggest that with resistant illnesses the prescription of a series of drugs one after another at the usual doses is the therapeutic strategy, rather than giving one drug only in progressively increasing amounts to the limit of tolerance. Of course, the doses recommended by drug companies are understandably cautious and sometimes excessively so. For example, MIMS (November 1982) gives for “Anafranil” (Geigy); “More severe cases, 75 mg daily or more if necessary” and for “Surmontil” (M & B) “50–75 mg as single dose”.

A randomized double blind group comparison study of sulpiride and amitriptyline was carried out in 36 patients suffering from major depressive disorder (DSM III critieria). Sulpiride showed equivalent antidepressant activity to amitriptyline at 4, 6 and 12 weeks, using the Hamilton Rating Scale (HRS) and the Wakefield Self-Rating Scale for depression (WRS). However, at 24 weeks the antidepressant activity of amitriptyline was just statistically significantly better than that of sulpiride. Timing of onset of action was comparable in both drugs. The anxiolytic activity of sulpiride was equivalent to that of amitriptyline at 4, 6, 12 and 24 weeks using the Salkind Manifest Anxiety Inventory as a measure. There were no significant differences between the two groups, of variables measured by the Crown-Crisp Experiential Index, a life events scale and Paykel's Social Adjustment Scale.

The concentrations of 3 putative neurotransmitters (glutamate, aspartate and γ-aminobutyrate), 4 related amino acids and 5 non-transmitter-related amino acids have been measured in neurosurgical samples (frontal cortex) from patients with intractable depression and controls. In addition, the glutamate receptor agonist 2-amino-4-sulpho-butanoic acid (homocysteic acid) has been identified in human brain and measured in these samples. There were no changes in the concentrations of amino acids in depressed patients compared to control with the exception of aspartic and homocysteic acids which were elevated in a sub-group of patients with depression compared to control. The Ca 2+ -dependent release (K + -stimulated) of putative neurotransmitters has been demonstrated for the first time from brain tissue of depressed patients. Glutamate release was unaltered from the control value. Aspartate values showed unexplained variability but it's release and that of γ-aminobutyrate were elevated in some depressed subjects. These results do not support the hypothesis of reduced amino acid function in depressive illness.

SummaryThe pneumo-encephalographs and computerized axial tomography scans of fifty patients with severe affective disorder were studied. Measures of ventricular size were compared with those reported by other workers. Findings suggested that some patients suffering from severe affective illness showed abnormalities of brain structure as demonstrated by ventricular enlargement.

The results of stereotactic subcaudate tractotomy in nine patients with resistant bipolar affective disorder are presented in the form of a single case study with a summary of the other eight cases. Follow-up studies at 2–4 years showed substantial improvement in five patients and amelioration of symptoms in a further four patients, with a tendency for a greater improvement in the manic than in the depressive episodes. These preliminary results suggest that there is a place for this operation in the management of severe bipolar affective disorders which are not responding to any other treatment, although decisive recovery occurs less often than with unipolar depression.

There is a pervading resistance in psychiatry to the adequate use of medication. Treatment-resistant depressive illnesses are widely accepted as such with little clinical challenge, although a good deal can usually be done to help patients with these distressing conditions. Two possible reasons for this tolerance of apparent untreatability are that (a) psychiatric disorders have a tradition of chronicity and (b) not all clinicians are inspired by the advent of psychopharmacology, which has offered potent treatment for illnesses that were previously hopeless. It is certain that many psychiatrists are mainly interested in psychodynamic approaches, which were likely to have been of prime importance during their training, and they tend to use medication only as adjunctive treatment.

SynopsisTryptophan and 5-hydroxyindoleacetic acid (precursor and metabolite respectively of 5-hydroxytryptaminę) were determined in ventricular CSF of psychiatric patients undergoing stereotactic subcaudate tractotomy. Tyrosine and homovanillic acid (precursor and metabolite respectively of dopamine) were also determined. Results suggest an association between affective state and the above precursor amino acids with lower concentrations in primary depression and higher ones when anxiety or agitation predominate. This leads to lower 5-hydroxyindoleacetic acid concentrations in depression and higher concentrations in anxiety and agitation.

SummaryThe routine air ventriculograms of 66 psychiatric patients, aged from 22 to 73 years, taken during the psychosurgical operation of stereotactic subcaudate tractotomy, were studied. Ventricular size was unrelated to progressive ageing, but a minority of patients over 60 years had abnormally large ventricles, not invariably associated with cognitive impairment on testing. Enlargement was associated with a clinical diagnosis of schizoaffective illness but not with past ECT.

SummaryThe aim of the study was to explore the way psychiatric symptoms might influence independent psychiatric assessment of outcome one year after stereotactic subcaudate tractotomy. In a sample of 34 patients consecutively accepted for psychosurgery the results showed that both ‘good’ and ‘poor’ outcome groups improved overall. No patients were significantly worse and the symptoms which improved most were nervous tension, depressed mood and somatic anxiety. It was not possible to identify symptomatic predictors of outcome because the preoperative symptom profiles of both groups were so similar. The reason why symptomatic outcome is so variable despite a basically identical psychosurgical technique is discussed.