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What's new in Affective Disorders?
Writing this short review has been made much easier by virtue of CK's role as Editor in Chief (with Prof Hagop Akiskal) of the Journal of Affective Disorders which is now the Section's official journal. CK has also had the opportunity to edit (with Prof Greg Simon) the Affective Disorders component of Current Opinion in Psychiatry for the last three years.
The review draws heavily on the summaries provided in Current Opinion. Research in affective disorders, as indeed in psychiatry as a whole, can conveniently be classified into four main areas: phenomenology and classification, aetiology, comorbidity, and management. We will review some of the (considerable) advances in each of these areas in turn.
Can there really be anything new to say about the symptoms and signs of affective illness or how they should be subclassified? Surprisingly, the answer is an emphatic 'yes'. Our understanding of the chronic but (so we thought) relatively mild depressions known as dysthymia has, in particular, advanced considerably. Rihmer's (1999) review reveals how profound our misconceptions have been about the by no means mild disorders at the periphery of major depression. He argues that dysthymia is a primary mood disorder with a mainly biological rather than psychosocial or psychodynamic basis. Akiskal's work (Akiskal et al 1997) fundamentaly reformulates dysthymia as a chronic, fluctuating primary mood disorder. Most of the biological abnormalities previously described in major depression, including changes in P300 amplitude on EEG (Murthy et al 1997) and platelet MAO activity (Tripodianakis et al 1998) also occur in dysthymia. Equally important, it is now clear that dysthymia responds well to antidepressant pharmacotherapy (Thase 1998) which should be given at full dose.
At the other 'extreme' of depression there remains fruitful debate as to whether depression complicated by delusions deserves a separate subclassification. Serretti's group (Serretti et al 2000; Lattuada et al 1999) found that patients with delusions had significantly more 'core' depressive symptomatology but responded similarly to treatment. These findings are in keeping with those of Muller et al (1999) in Germany. It is unsurprising, therefore, that newer antipsychotics alone are inadequate treatment for mood congruent delusions ((Muller-Siecheneder et al 1998). More surprising perhaps is the finding that SSRIs may be particularly effective in patients with delusional depression (Zanardi et al 2000).
Biological markers of depression remain a fruitful area of study. Platelet marker studies of the 5HT system remain inconclusive, though the study of prepubertal children by Pfeffer et al (1998) add further weight to the notion that platelet serotonin measures may be abnormal in patients with marked suicidal ideas. Single Photon Emission Tomography (SPET) has enabled serotonin function to be studied directly in living human brain, thus avoiding many of the problems confounding previous work on peripheral 5HT markers or in post-mortem tissue. Malison et al (1998) used radio-iodinated citalopram to quantify serotonin transporter activity in depressed subjects before and after treatment and reported a reduction in uptake sites in the brain stem of depressed patients which normalised with treatment. There is also emerging evidence for genetically determined variability in serotonin transport regulation (Lesch and Mossner 1998). Catecholamine studies have focused mainly on platelet adrenoceptors. Newly emerging adrenoceptor subtypes may be particularly important. Piletz et al (1996) for example suggest that the I1 subtype of imidazolamine receptor may be increased in the platelets of untreated depressed patients and normalise with treatment.
Immunological studies in depression continue to proliferate. Proinflammatory cytokines rise in depression and normalise with treatment (Sluzewski et al 1995); interleukin-2 receptor mediated blastoformation on the other hand is suppressed in depressed patients ( Kanba et al 1998) but also normalises with treatment.
Neuroendocrine research in affective disorders continues to focus mainly on the hypothalamo-pituitary-adrenal system but the emphasis is increasingly on the 'top end'. More specific 'probes' for 5HT subtypes show promise: blunted growth hormone response to sumatriptan in depression (Cleare et al 1998) suggests a specific abnormality in 5HT1D receptors. Studies by Scott and Dinan (1998) suggest that vasopressin challenge tests may be a better probe than dexamethasone or CRF as a test for depression-specific abnormalities in HPA axis function. Dinan (2001) argues that prolactin release to 5HT agonists may be a better marker of aggressivity than of depression, citing the work of Correa et al (2000) on patients with a history of suicide attempts and that of Fava et al (2000) on patients with 'anger attacks'. He considers that the HPA axis remains a legitimate focus for biological research in depression (and bipolar disorder). HPA axis changes may predict first episodes or relapses and there is growing evidence that normalising HPA function is effective in refractory depression (Wolkowitz and Reus 1999). Dinan concludes by suggesting, tantalisingly, that a new generation of antidepressants may in future target the HPA axis rather than monoamines.
A recent review by Reid and Stewart (2001) attempts to draw together threads from molecular and physiological studies in animals as well as neuroendocrine and neuropsychological studies in man to suggest that the primary action of antidepressants may be to reverse the neurotoxic effects of stressors on individual neurotrophin mediated neuronal growth activity and on the plasticity of neural networks. In this innovative model (which, like Dinan's work, suggests a range of novel therapeutic targets beyond the monoamines, chronic depression is conceptualised as a neurodegenerative disorder which early and vigorous treatment of acute episodes might prevent.
Both detection and management of depression can be particularly problematic in the context of comorbid medical illness. Anhedonia, low positive affect and high physiological arousal may be useful pointers to the presence of depression in medical patients (Clark et al 1998). The main risk factors for depression in physically ill patients (apart from severity of the physical illness itself) are the same socio-demographic variables (social isolation, poverty, past history of depression) that predispose to depression in physically healthy people (Koenig 1997). In the specific context of post-stroke depression, there is increasing evidence that previous reports of increased risk of depression following left-sided lesions may have been misleading and secondary to differences in the effect of lesion location on the ability to express depressive symptoms verbally (Gainotti et al 1997). Treatment trials have concentrated on antidepressants and attest, generally, to their efficacy as well as to the superior safety profile of SSRIs (Roose et al 1998).
Depression in primary care is emerging as an important research area, and one which can also be conceptualised in terms of comorbidity. Araya (1999) suggests that such depression may usefully be conceptualised as a different illness to 'hospital' depression with, in particular, more fatigue but fewer psychological symptoms. Prospects for improved management of primary care depression are good however in the light of evidence that both antidepressants a range of relatively simple psychological techniques including problem-solving (Mynors-Wallis et al 2000) and brief cognitive therapy (Scott et al 1997) are effective. Brief psychotherapies have also been shown to be superior to 'usual treatment' in depressed primary care patients (Ward et al 2000). The superiority of structured treatments may be due in large part to improved adherence (Peveler et al 1999, Simon et al 2000). Future primary care research outcome studies will use more appropriate outcome measures and include economic evaluation.
Depression resistant to treatment is still a major clinical problem, and research into specific treatments for refractory depression remains continues to proliferate. O'Reardon et al (2000) point out that, now that SSRIs are increasingly used as 'first-line' treatment, strategies are now needed for managing lack of response to this group of drugs. Surprisingly, similar responses are reported to switching to another SSRI, switching to another class of antidepressant, and adding lithium (Nelson 1998, Thase et al 1998). Evidence for more novel approaches such as pindolol augmentation (Soler et al 1999) or buspirone (Landen et al 1998) is, unfortunately, much weaker.
Relapse prevention, both in unipolar and bipolar disorder remains a major challenge. In bipolar disorder, anticonvulsants are increasingly used though recent controlled studies suggest that lithium is as effective as valproate (Bowden et al 2000) and superior to carbamazepine (Moleman et al 2000). The efficacy of lithium in preventing recurrence in unipolar depression is confirmed by the metaanalysis of placebo-controlled and 'mirror-image' studies by Davis et al (1999) and by a recent controlled trial of continuation treatment with lithium in combination with antidepressants (Bauer et al 2000). The SSRI citalopram has recently been shown (in a randomised comparison with placebo) substantially to delay recurrence in patients with a history of recurrent depression whose acute illness responded to open-label treatment with citalopram (Hochstrasser et al 2001). Similar results have been reported for another SSRI, paroxetine (Franchini et al 1998). The synergistic effect of antidepressants and Interpersonal Psychotherapy, well documented in younger patients by the Pittsburgh group, has now been shown to be similar in preventing recurrence in older patients at high risk (Reynolds et al 1999).
This brief review indicates that research in affective disorders is varied and flourishing. A new research organisation, the International Society for Affective Disorders (ISAD), has just been launched and will hold its inaugural meeting in Taormina, Sicily in March 2002. ISAD will bring together researchers from different disciplines and facilitate the development of a rational research agenda in the field. Collaboration will also be facilitated through web-based discussion. Active researchers in the field are welcome to join ISAD - visit the website on www.isad.soton.ac.uk. Membership includes personal subscription to the Journal of Affective Disorders, which is now it's house journal as well as that of our Section.
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