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The use of neurosurgery for mental disorders (NMD) is a clinical issue that involves many ethical considerations. It is a treatment that offers hope for many patients with severe and debilitating affective and anxiety disorders and should be widely available. Its current use worldwide (UK, Sweden, US, Australasia, Europe) is reviewed and the types of procedures currently used are explained (stereotactic subcaudate tractotomy, anterior capsulotomy, cingulotomy, limbic leucotomy). In addition, clinical strategies for the evaluation and management of patients both prior to and following NMD are discussed.

The inadequate assessment and management of depression can lead to the erroneous diagnosis of treatment resistance. After briefly considering the definition and diagnosis of resistant depression, the authors describe the principles and methods of antidepressant therapy, emphasizing the systematic use of medication and the importance of therapeutic drug monitoring. The application of these is then discussed in a clinical context, and illustrated with examples.

The Geoffrey Knight National Unit was set up in 1970 exclusively for psychosurgery. In recent years it has become increasingly concerned with the development of medication regimens that might avoid the need for surgery. This has offered a unique pharmacotherapeutic opportunity because all the referrals have severe, persistent and treatment-resistant disorders. The scheme of high-dose and combined medication devised is presented and discussed.

This 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.

Background: Stereotactic 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., Method: Relevant 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., Results: SST allows 40-60% of patients to live normal or near-normal lives, perhaps with continuation of medication. A reduction in suicide rate to 1% post-operatively, from 15% in cases of uncontrolled affective disorders is seen., Conclusion: As 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.

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.

Stereotactic subcaudate tractotomy is a surgical procedure performed for the alleviation of intractable affective disorders. It involves the destruction of bifrontal pathways located beneath and in front of the head of the caudate nucleus. We report the first prospective study of the neuropsychological correlates of this operation in 23 patients. Tests of general intelligence, speed and attention, as well as a wide range of focal cognitive tests, including tasks which have been reported in the literature to be sensitive to frontal lobe dysfunction, were administered 1 wk before the operation, 2 wks after the operation and approximately 6 mths after the operation. The results indicated that this operation does not cause any significant, long-term adverse, cognitive deficits. In the post-operative assessment, however, patients show a significant deterioration in their performance on recognition memory tests and a large proportion of them present with a marked tendency to confabulate on recall tasks. In addition, their performance on some of the tasks which are considered to be sensitive to frontal lobe dysfunction is found to be significantly impaired. These deficits are interpreted to reflect frontal lobe dysfunction due to widespread post-operative oedema rather than damage to the subcaudate pathways. The potential for research on these transient effects of the operation for the advancement of our understanding of frontal lobe functions is discussed.

Tyramine sulphate conjugation following oral tyramine administration (the tyramine test) has previously been found to distinguish endogenous unipolar from neurotic depression and appears to be a trait marker. In this study, the test was used in 24 unipolar depressed patients compared with similar sized matched groups of bipolar depressed patients and normal controls. Most of the depressed patients in each group showed endogenous features. The study found that whereas tyramine sulphate conjugation was significantly impaired in unipolar patients, values in the bipolars were similar to those of controls. These results provide further evidence for the biological difference between unipolar and bipolar depression.

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.

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.

The antidepressant efficacy, influence on sleep variables and incidence of side-effects of trazodone (100-400 mg daily), given either as a single night-time dose or thrice daily, were compared in a double-blind, 4 week, parallel group, multicentre hospital study. Of 56 patients who entered the study, full data was available for 37, of whom 20 took the medication at night and the other 17 received divided doses during the day. The results showed equivalent therapeutic efficacy for the two dosage regimens and tolerance was good in both groups. For onset and also duration of sleep, significantly more patients in the single night-time group improved than worsened in response. Both groups of patients tended to report a more satisfying sleep and greater freshness on waking, although these latter effects were not statistically significant. For the group taking trazodone thrice daily, there was a trend for more complaints of side-effects, particularly dry mouth, headache and drowsiness which led to more of these patients requiring modification of dosage. Thus trazodone appears to have clinically useful sedative properties. It has relatively few side-effects and these are generally reduced by giving a single dose at night.

The psychosurgical operation of stereotactic subcaudate tractotomy can be a highly effective treatment for chronic and intractable affective disorders. We have lately given increasing attention to cases where the depressed mood appears to lift although there is little improvement in social function. In these cases there has been a failure of rehabilitation and the complexities of this process post-operatively are discussed. In addition, relatives report in some 10% of cases "personality changes" after the operation which are not perceived in this way by an independent medical assessor and these observations seem to depend upon relatives mis-interpreting the resumption of pre-morbid personality function after long illnesses as undesirable side-effects. Case histories illustrating the problems are described. Treatment and rehabilitation strategies are outlined.

A randomized double blind group comparison study of sulpiride and amitriptyline was carried out in 36 patients suffering from major depressive disorder (DSM III criteria). 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 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 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.

To assess the possible significance of cerebral ventricular size and the dexamethasone suppression test (DST) in the outcome of severe endogenous depression, 28 patients were followed up and reviewed 1 year after stereotactic subcaudate tractotomy. Neither ventricular size nor the dexamethasone suppression test predicted either a good or poor outcome. There was no relationship between ventricular size and the DST results.

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 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 alpha adrenoceptor functions in depression, and the effect upon this of antidepressant treatment.

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.

In a 6-week double blind non-crossover study, trazodone and imipramine have been compared in the treatment of patients with severe endogenous depression. By random allocation, 13 patients entered each treatment group. The mean maintenance dosage of trazodone was 300 mg (range 200-350 mg) and of imipramine 160 mg (range 150-175 mg). Some evidence is presented to suggest that trazodone may have an earlier anxiolytic effect than imipramine by day 4 and a greater antidepressant effect by day 22 of treatment. Apart from the frequency of impaired visual accommodation being significantly greater in the imipramine group, there were no differences between the treatments with respect to side-effects. No abnormalities were found from laboratory investigations and ECG assessments.

The concentrations of 3 putative neurotransmitters (glutamate, aspartate and gamma-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 Ca2+-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 gamma-aminobutyrate were elevated in some depressed subjects. These results do not support the hypothesis of reduced amino acid function in depressive illness.

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.

Fifty consecutively admitted male alcoholics (mean age = 42.8 +/- 8.5 years) were selected. This study shows objectively that 31/50 chronic alcoholics (62%) were found to be severely depressed (Hamilton Depression Rating Scale (HRS) greater than 22); 12/50 (24%) moderately depressed (HRS = 16-22); and 7/50 (14%) were not depressed (HRS less than 15). According to dexamethasone suppression test (DST) results, 8 out of 50 patients showed escape from suppression with 2 mg dexamethasone while 42/50 showed normal suppression. Depression in alcoholics may be of neurotic type or it may be ethanol-induced reactive depression. Raised cortisol levels and abnormal DST response showed a definite tendency towards normalisation after total abstinence accompanied by clinical improvement of depressive symptomatology. The DST showed improvement on improvement of mood and sleep in these patients during total abstinence. An abnormal DST response in chronic alcoholics seems to be state-related and not trait-dependent; it seems to be a non-specific test for depression in alcoholics. Hepatic status was affected equally in both suppressors and non-suppressors of DST. It is therefore suggested that abnormal DST in alcoholics may be due to the abnormality of the hypothalamo-pituitary-adrenocortical (HPA) axis and not due to abnormal hepatic function or histological status.

Patients with endogenous unipolar depressive illness show a highly significant decrease in ability to metabolize an oral load of tyramine to its sulphate conjugate compared with controls and neurotic depressives. As this biochemical lesion persists after clinical recovery and is present in about half the non-depressed first degree relatives of endogenously depressed probands, it is likely that the abnormality is a trait marker for depressive illness. It may thus be useful in practice as a predictor of vulnerability to depressive illness. The tyramine test is superior to the dexamethasone suppression test in both sensitivity to, and specificity for, endogenous depression.