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EDITORIALS: Andrea Cipriani, John R Geddes, and Corrado Barbui Venlafaxine for major depression BMJ 2007; 334: 215-216 [Full text]

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Suicidal and self-harming behaviours may be distinct, separate entities.

Philip V Dutton, Andrew J Ashworth   (7 February 2007)

S.N.R.I. Effect by Combination Therapy

James Paul Pandarakalam   (9 February 2007)

Identifying and treating Bipolar Illness Early.

Mark Agius, Giuseppe Tavormina   (19 February 2007)

The risks of treating serious illness

Trevor H Turner   (22 February 2007)

Suicide risk and choice of antidepressant.

Abigail Davis, Michael Gilhooley, Mark Agius   (23 February 2009)

Suicidal and self-harming behaviours may be distinct, separate entities. 7 February 2007
Philip V Dutton, Consultant Clinical Psychologist Synapse, 15b Barnton Street, STIRLING FK8 1HF, Andrew J Ashworth Send response to journal: Re: Suicidal and self-harming behaviours may be distinct, separate entities.	We were pleased to see the recognition that deliberate self harm, while often thought to be a hard outcome in studies, includes a number of different entities. However, we believe that it is important to classify the method as well as the motivation of self-harm since the physiological mechanisms involved lead to different perceived and actual outcomes. Table one summarises the conditions that apply to outcome. If the motivation is truly suicidal, a non-fatal outcome is unsuccessful but where the motivation is not suicidal, death is accidental. We might also observe that those with suicidal intent using highly lethal, less painful methods are likely to die, making only the “failed” suicidal group available for academic study (often recruited following hospital presentation). Overdoses of drugs or poisons are more likely to be lethal and, if unsuccessful, to result in hospital admission whereas self-harm involving physical injury such as cutting or hitting an inanimate object is more commonly encountered in the community. Suicide numbers in studies can be increased by including those who injure themselves using low lethality, highly painful methods but suicide studies require differentiation between these groups to retain validity. If self-harm patients who die accidentally are included this will have a skewing effect on post mortem studies of suicide. Studies on true suicide survivors should not include those who had not intended to die but who had other motivation (we would argue a normalisation of mood through behaviour that increases the level of circulating endogenous endorphins) for their self-harming behaviour. TABLE 1. Method versus Outcome measures in terms of Suicide and Survival. Method Outcome Death Survival High lethality Low Pain Successful (Suicide) N = large Failed (Attempted Suicide) n = small Low Lethality High Pain Failed (Accidental Suicide) n = small Successful (Survival) N = very large In our clinical practices in the community we recognise a significant number of patients who regularly use low-lethality high-pain methods such as cutting, scratching or other physical trauma to modify mood. We have previously hypothesised an aetiology for this self-harm based on an imbalance of endogenous opioids (1) and have developed a treatment involving the temporary normalisation of endogenous opioid neurochemistry to create a brief window of opportunity for successful psychotherapy. Reductions in self-harm behaviours were achieved by the use of low frequency TENS (2) for a limited time during which subsequent resolution of self harm behaviour and urges was achieved using psychotherapy (3). In these cases we assumed a psychological stimulus for the enduring opioid imbalance and used Shapiro’s concept of Adaptive Information Processing to address the root problems with trauma-specific Eye Movement Desensitisation & Reprocessing (EMDR) (4). (1) Ashworth AJ. Endogenous Opiate Activity Imbalance - a Physiological Basis for Psychosocial Dysfunction? http://www.bmj.com/cgi/eletters/bmj.38790.495544.7Cv1#131910 (2) Han, J S. Chen, X H. Sun, S L. Xu, X J. Yuan, Y. Yan, S C. Hao, J X. Terenius, L. Institution Effect of low- and high-frequency TENS on Met-enkephalin-Arg- Phe and dynorphin A immunoreactivity in human lumbar CSF. Pain. 47(3):295-8, 1991 Dec. (3) Dutton P V Unpublished case study. (4) Shapiro F (2001). Eye Movement Desensitisation and Reprocessing: Basic Principles, Protocols and Procedures. (second edition). Guilford. Competing interests: None declared
S.N.R.I. Effect by Combination Therapy 9 February 2007
James Paul Pandarakalam, consultant psychiatrist, 5 Borough Partnership NHS Trust St Helens North CMHT, Peasley Cross Resource Centre, St Helens, Merseyside WA 9 3DA Send response to journal: Re: S.N.R.I. Effect by Combination Therapy	It was at a point of recognition that S.S.R.Is are not as effective as tricyclic antidepressant therapy in certain subsets of depressed patients, indicating the importance of nor epinephrine re uptake inhibitors, S.N.R.Is were introduced. There is evidence from controlled investigations that venlafaxine, an S.N.R.I. is effective in managing major and refractory depression 1,2, but unfortunately it is now being associated with higher suicidal risk and toxic side effects. The relative toxicity of venlafaxine overdose compared with other antidepressants have been already highlighted 3.The alleged suicidal attempts associated with venlafaxine in comparison with S.S.R.Is could be due to the NRI component. Noradrenaline may preferentially improve vigilance, motivation and self- perception. TCA therapy is associated with relative risk but reboxetine has a good safety profile. Combining an S.S.R.I with reboxetine could compose an S.N.R.I effect in order to treat major depression. Such a procedure has the advantage of possessing a hold on the N.R.I effect by adjusting the dose of reboxetine. The safer side effect profile of reboxetine bodes well for long term patient compliance. Reboxetine is not cardiotoxic and it is not associated with an increased risk of seizures or orthostatic hypotension. Reboxetine has mild anticholinergic effects and produces sexual side effects. It is safer in overdose and seems to have negligible interference with the pharmacokinetics of other drugs. In the olfactory bulbectomized rat model of depression, reboxetine, sertraline and their combination were tested and, the combination treatments had better outcome . 4 Sertraline has only mild anticholinergic effects and no sedative effects. It is supposed to be relatively safe in cardiac conditions, liver impairment, diabetes mellitus and seizure disorders. Making a dual action antidepressant by combining sertraline and reboxetine appear to be a safer method of managing treatment resistant depression. Other S.S.R.Is could also be combined with reboxetine to make an S.N.R.I. When switching antidepressant drugs, one of the problems is discontinuation symptoms and also disappointment from the part of the patients that they have lost some initial benefits gained out of the first drug in addition to the disadvantage that patient has to cope with another waiting period for the substituted drug to produce desirable results; combination therapy is the answer to these problems. Obviously, combination therapy is not without the disadvantage of drug interactions. References: 1.Nolen ,W.A, Van de Putte,J.J., Dijken,W.A. Treatment strategy in depression.2.MAO inhibitors in depression resistant tricyclic antidepressants: two controlled cross-over studies with tranylcypromine versus 1,5-hydroxytryptophan and nomifensine. Acta Psychiatrica Scandinavica. 1988; 88:278-85. 2.Poirier,M.F., and Boyer, P. Venlafaxine and paroxetine in treatment resistant depression, Double blind, randomised comparison. British Journal of Psychiatry 1999; 175:12-16 3.Buckly NA, McManes PR. Fatal toxicity of seronergic and other antidepressant drugs. Analysis of united kingdom mortality data. BMJ 2002; 325: 1332-1333 4.Harkin A,Kelly JP, McNamara M,Conner TJ, Dreg K,Leonard BE. Activity and onset of action of reboxetine and effect of combination with sertraline in an animal model of depression. Eur J. Pharmacology. 1999; 364 (2-3):123-32 Competing interests: None declared
Identifying and treating Bipolar Illness Early. 19 February 2007
Mark Agius, Associate Specialist Bedfordshire and Luton Partnership Trust, Giuseppe Tavormina Send response to journal: Re: Identifying and treating Bipolar Illness Early.	Smith et al are to be congratulated in drawing attention to the possibility that the increased risk of suicide in patients treated with Venlafaxine may be explained by undiagnosed bipolar disorder in the group of patients under consideration.[1].Thus the key problem exposed by the epidemiological facts identified by Rubino et al [2] does not appear to lie with the medication itself but with the unmasking of occult bipolarity by Venlafaxine. It is known that bipolar disorder, of both the type I and Type II sort, is often underdiagnosed and undertreated.[6] There is evidence that many patients with bipolar illness have a long duration of untreated illness analogous with the Duration of Untreated Psychosis in other psychotic illnesses.[3] There is evidence that if a series of patients with unipolar depression are followed up over time, some, at a constant rate, gradually change to cases of bipolar affective disorder.[4] The long durations of untreated illness in bipolar affective disorder have given rise to concern. [3] Attempts are being made to develop a pattern of early symptoms, analogous to the ‘Prodrome’ of Schizophrenia, to help identify patients who are developing early bipolar disorder[5]. In practice, early bipolar disorder will be identified and treated if Primary Care Doctors are effective in identifying and treating early cases of depression or bipolar disorder which present to them. [6] We would suggest that care should be taken that , each patient who presents with major depression, both in primary and secondary care is asked to identify any period of elated mood which they have experienced, even if this has lasted for only a few days. A family history of bipolar illness or suicide, previous episodes of hypomania, at least three recurrent depressive episodes, cyclothymia, and a seasonal onset [winter in bipolar II and summer in bipolar I patients], have all been identified as indicators of the possibility of bipolar illness [7]. Identifying these markers will enable patients with bipolar illness to be identified, perhaps earlier than they otherwise would. The cautions that antidepressant monotherapy for bipolar disorder may precipitate hypomanic or mixed states, which are strongly associated with self harm and completed suicide , and that Venlafaxine seems more likely than other antidepressants to precipitate a switch to mania in bipolar depression [1] should then lead to a policy that, once bipolar depression is identified earlier, mood stabilisers , including Lithium, should be considered to treat the illness [8][9], rather than anti-depessants [including Venlafaxine] alone. We would suggest that a policy of early diagnosis and appropriate treatment of bipolar disorder is likely to be the most effective step that we can take. Caution regarding the use of Venlafaxine as a first line treatment in unipolar depression [10] must be seen as secondary to this. References [1] Smith D, Walters J [2007] Bipolarity is important during treatment with antidepressants. BMJ 334;327. [2] RubinoA, Roskell N, Tennis P, MinesD, Weich S, Andrews E. Risk of suicide during treatment with Venlafaxine, citalopram, Fluoxetine and Dothiepin; retrospective cohort study . BMJ 2007;334 242-245. [3] Vlazquez-Barquero J et al [2006] Early Intervention in Bipolar Disorders: Rationale for the overdue implementation of a fesable paradigm. Schizophrenia Research 86 S 36 [4] Angst J, Sellaro R [2000] Historical perspectives and natural history of Bipolar Disorder. Soc Biol Psychiatry 48; 445-457. [5] Conus P et al [2006] The prodrome to first episode psychotic mania ; results of a retrospective study. Schizophrenia Research 86 S 37. [6] Agius M, Erithrajalu R, Mani B [2006] The diagnosis and treatment of bipolar and other affective disorders within the model of Early Intervention Services. The second dual congress on Psychiatry and the Neurosciences, 1st European Congress of the International Neuropsychiatric Association ; 2nd Mediterranean congress of the World Federation of Societies of Biological Psychiatry Athens 2006 Book of Abstracts p 49. [7] Tavormina G [2006] The approach to Bipolar Spectrum Diagnosis . The second dual congress on Psychiatry and the Neurosciences, 1st European Congress of the International Neuropsychiatric Association ; 2nd Mediterranean congress of the World Federation of Societies of Biological Psychiatry Athens 2006 Book of Abstracts p 48. [8]Akiskal H [2006] Bipolar Depression; the long term view. The second dual congress on Psychiatry and the Neurosciences, 1st European Congress of the International Neuropsychiatric Association ; 2nd Mediterranean congress of the World Federation of Societies of Biological Psychiatry Athens 2006 Book of Abstracts p 30. [9] Rihmer Z, Gonda X. [2006] Prediction and prevention of suicide in bipolar illness. The second dual congress on Psychiatry and the Neurosciences, 1st European Congress of the International Neuropsychiatric Association ; 2nd Mediterranean congress of the World Federation of Societies of Biological Psychiatry Athens 2006 Book of Abstracts p 30. [10] Cipriani A, Geddes J, Barbui C. [2007] Venlafaxine for major depression. BMJ 334 ;215. Competing interests: None declared
The risks of treating serious illness 22 February 2007
Trevor H Turner, Consultant Psychiatrist City & Hackney Centre for Mental Health E9 6SR Send response to journal: Re: The risks of treating serious illness	Any medication deemed to be the “strongest” or “most effective” for the treatment of an illness such as depression will by definition be linked with higher rates of suicide, given the close association between severity of depressive illness and likelihood of suicide. Because of its dual action in terms of serotonin reuptake as well as noradrenalin reuptake, Venlafaxine has been marketed, particularly in its earlier days, as a second line drug for the treatment of more resistant depressions, for example in patients not responding to other SSRIs. This is reflected in the finding that Venlafaxine users, in the study by Rubina et al, had a higher burden of suicide risk factors. The history of antidepressant prescribing shows a consistent relationship between the most successfully marketed drug (e.g. Prothiaden in the 1970s / 80s) and suicide risk. This association with a negative outcome (i.e. suicide) holds throughout medicine. The surgeon who is prepared to operate on the more difficult cases, for example elderly diabetics, is clearly going to be at more risk of having post-operative complications than the surgeon who stays with healthy young adults. Psychiatrists working in socially deprived, inner city areas are likely to experience more ‘untoward incidents’, in terms of their patients getting involved in violence, because of the nature of the community into which those patients are discharged. The suggestion therefore in your editorial ‘Venlafaxine for major depression’ that “Venlafaxine should not be first-line treatment for people with major depression” would seem to have got the wrong end of the stick. It is not because it has been used as a regular first-line treatment, but rather as an attempt to deal with a non-responding illness, that it has now got its suicide association soubriquet. Should manufacturers therefore be advised not to market their products as the most effective antidepressant, in future, since by definition a successful marketing campaign will land them with the suicidality label? Competing interests: None declared
Suicide risk and choice of antidepressant. 23 February 2009
Abigail Davis, Medical Student Clinical School University of Cambridge, Michael Gilhooley, Mark Agius Send response to journal: Re: Suicide risk and choice of antidepressant.	In view of the findings of Cipriani [1] and Rubino [2], we wished to find out whether suicide risk, in terms of either previous suicide attempt or suicidal ideation , influenced the choice of antidepressant in an outpatient mental health unit in Bedford. An anonimised database of two consultants’ current outpatients was filtered using Microsoft® Excel® to give a sample of patients with a confirmed ICD-10 diagnosis of either acute depressive episode F32 or recurrent depressive disorder F33 and who were currently prescribed either Citalopram or Venlafaxine monotherapy (n=50). There was more venlafaxine prescription;31 were prescribed Venlafaxine and 19 were prescribed citalopram.This probably reflects that this is secondary care, GPs may have trialled citalopram prior to referal. Individual patient records were then reviewed and assessed for history of suicidal ideation or attempt. Six patients prescribed venlafaxine had made a suicide attempt compared with three prescribed citalopram. Three patients prescribed venlafaxine had had suicidal ideation, as had four on citalopram.It was shown that, in this sample, neither a history of suicidal ideation nor of suicide attempt prevented venlafaxine prescription – in line with current opinion. In a second study, we used the whole database to study 94 patients on monotherapy for depression. Forty-eight were male and 46 female. Six males [12.5%] were on Venlafaxine, as were nineteen females [41.3%]. Gender is a significant risk factor for suicide. Suicide is 3 times more common in men than in women. Correspondingly, in this sample less males are on Venlafaxine than females. In a final study we identified ten patients in the database who had a diagnosis of Bipolar II disorder and were taking Venlafaxine. All of these patients were also taking a mood stabiliser, either Lithium or Valproate. Thus in our audits, we could show what appears to be safe practice in the prescription of Venlafaxine. We suggest that such audits will ensure that Venlafaxine is used in an effective and safe way. References [1] Cipriani A, Geddes J, Barbui C Venlafaxine for major depression BMJ 2007; 334: 215 - 216 [2] Rubino A, Roskell N,Tennis P, Mines D, Weich S, AndrewsE Risk of suicide during treatment with venlafaxine, citalopram, fluoxetine, and dothiepin: retrospective cohort study BMJ 2007; 334: 242 Competing interests: None declared