PSYCHOSOCIAL AND BIOLOGICAL INTERVENTIONS IN THE MANAGEMENT OF MOOD DISORDERS


Dr Alexis Bowers MBBS MRCPsych, Specialist Registrar in Old Age Psychiatry, Central and North West London NHS Foundation Trust, London, United Kingdom.

‘Mood disorders’ is a collective term relating to specific mental illnesses. Their main feature is an abnormality of mood. Contemporary descriptions of these disorders are usually restricted to episodes of depressed mood or elation.

Mood disorders have been variously described and classified throughout the ages. It was the Hippocratic School (ca. 370 BC) who provided the first scientific theories behind mood disorders and dispelled the notion of a supernatural or demonic aetiology. They asserted that mental illness occurred through the imbalance of ’humours’ in the body and treatment was aimed at rectifying this imbalance. Melancholia (or depression) was thought to be a result of excessive black bile and mania from excessive yellow bile. Given that contemporary research focuses upon neurotransmitter dysregulation in the aetiology of mood disorders their initial hypotheses were not entirely spurious (Ackenheil, 2001).

Richard Mead, an eighteenth century English physician, built upon this definition and further described depression and mania as follows:

“Medical writers distinguish two kinds of Madness, and describe them both as a constant disorder of the mind without any considerable fever; but with this difference, that the one is attended with audaciousness and fury, the other with sadness and fear: and that they call mania, this melancholy. But these generally differ in degree only. For melancholy very frequently changes, sooner or later, into maniacal madness; and, when the fury is abated, the sadness generally returns heavier than before.” (Jackson, 1986)

Falret (1854), a French psychiatrist, described a circular disorder (la folie circulaire) which describes bipolar disorder as we know it today. It was Karl Leonhard, in 1957, who distinguished two separate patient cohorts. Some patients had only recurrent depressive episodes whereas other patients had histories of depression and mania (and it was these whom he termed bipolar).

In his seminal work, Mourning and Melancholia (Freud, 1957), Sigmund Freud, an Austrian neuro-psychiatrist, discussed intrapsychic causes for depression and related early childhood experiences as an important factor for the later development of a depressive illness. It is now accepted that there is not just one aetiological pathogen but a combination of environmental factors and genetic vulnerabilities that contribute to the pathogenesis of mood disorders (Cooper, 2001).

Current nosiological classificatory systems include the International Statistical Classification of Diseases and Related Health Problems (version 10) and the Diagnostic and Statistical Manual of Mental Disorders (version 4) (American Psychiatric Association, 2000). These classify mood disorders into major depressive episodes and bipolar affective disorders.

Depression, as defined by the International Statistical Classification of Diseases and Related Health Problems (version 10) is a specific mental illness that is characterised by low mood, lack of energy and demotivation. It is commonly associated with somatic complaints (including a decrease in concentration, sleep disturbance, appetite disturbance and occasionally suicidal ideation. Bipolar disorder, similarly defined, is a cyclical mood disorder whereby the patient alternates between periods of depression and mania (characterised by an elevation of mood, increase in goal directed activity, over talkativeness and occasional social and sexual disinhibition). (World Health Organisation, 1994). Both illnesses, if untreated, are associated with significant psychological and physical morbidity.

With scientific advance, neuro-biological correlates of these illnesses are being discovered. Although as history shows, phenotypically these illnesses are very much similar, genotypically they are very much heterogeneous. In the future these terms may change and become more descriptive as the underlying aetiologies become apparent.

Classifying illness phenotypes (such as depression and bipolar) can assist researchers into developing novel treatments. An evaluation of current treatments will be presented below with available evidence that supports their clinical utility.

Contemporary treatments for depressive and bipolar illnesses are tailored to individual patients. UK medical practitioners follow national evidence based guidance for managing patients with mood disorders (National Institute for Clinical Excellence). Management can be catagorised into biological treatments (e.g. pharmacotherapy and electroconvulsive therapy), psychological treatments (e.g. cognitive behavioural therapy, interpersonal therapy) and social interventions (e.g. lifestyle changes). Newer treatments (e.g. vagal nerve stimulation) and herbal treatments (e.g. St John’s Wort) will also be evaluated. Setting for treatment is also important however for reasons of brevity this will not be covered in this essay.

PHARMACOTHERAPY

DEPRESSION

Antidepressants are the main pharmacological agents used to treat depression. Their common mode of action is to increase levels of central monoamines (in particular serotonin and noradrenaline). Deficiencies of these particular monoamines have been shown to be present in depressed subjects (van Praag et al 1971).

The main classes of antidepressants include tricyclics, monoamine oxidase inhibitors and selective serotonin reuptake inhibitors (SSRI's). There are now newer ‘third generation’ antidepressants (mirtazipine, reboxetine and venlafaxine) as well as an herbal preparation (St Johns Wort) that are used to relieve symptoms of depression.

Tricyclic antidepressants have been shown to be more effective than placebo (Morris et al 1974) in the treatment of depression. A meta-analysis of selective serotonin reuptake inhibitors has demonstrated comparable efficacy with that of tricyclics (Song et al 1993). Monoamine Oxidase inhibitors have also shown comparable efficacy to that of tricyclics and SSRI’s (Angst et al 1992). Venlafaxine has been shown to be useful for treatment resistant depression (Nirenberg et al 1994), however, in their full guideline, NICE conclude that there is not sufficient evidence supporting a superior efficacy over other conventional antidepressant agents (NICE, 2004). A recent meta-analysis reviewed all clinical trials submitted to the US Food and Drug Administration for the licensing of fluoxetine, venlafaxine, nefazodone, and paroxetine. They found little difference with these antidepressants compared with placebo except in patients with a severe depressive episode (Kirsch et al 2008). The placebo effect (the measurable, observable, or felt improvement in health or behaviour not attributable to a medication or treatment that has been administered) in patients undergoing treatment for depression has been reported to be as high as 75% (Kirsch et al 1998). St John’s Wort (SJW) contains at least 10 different components and the exact mode of action is unknown. The Cochrane database has reviewed available evidence concerning SJW and provides some evidence to support its use in mild depression. However, in severe depressive illness it has not been recommended (Linde et al 1998).

In severe cases of depression polypharmacy maybe indicated. Lithium has the most robust evidence supporting its use as an augmenter (Bauer et al 1999). Other augmentation agents that are used although have less of an evidence base include lamotrigine, (Calabrese et al 1999), pindolol (McAskill et al, 1998) and tryptophan (Young, 1991).

BIPOLAR AFFECTIVE DISORDER

Pharmacological treatment strategies for bipolar disorder are complex depending on stage and severity of illness. A full review with up to date evidence can be found in The Maudsley Prescribing Guidelines (Taylor et al 2007). Patients generally require treatment if they are manic or depressed. Current evidence supports the use of lithium, mood stabilisers and antipsychotics during manic phases of illness (Goodwin et al 2003). Treatment during this phase of illness is usually within a hospital setting to contain severe behavioural disturbance. Rapid tranquilisation may be required in this instance where agents are administered parenterally. There is no uniform consensus as to which agents should be used however a sedating intramuscular antipsychotic preparation is available (olanzapine). Benzodiazepines can also be used to decrease arousal during this phase (Curtin et al 2004).

The use of antidepressants in the pharmacological treatment of bipolar depression remains controversial. Used as monotherapy there is evidence to support an increased rate of switching to the other pole especially if tricyclic antidepressants are used (Peet, 1994). Recommended guidance is if antidepressants are given, mood stabilisers should also be administered to minimise this risk (NICE, 2006). Lithium provides the most robust evidence for acute treatment of bipolar depression however individual patient characteristics must be taken into account when deciding on a particular agent (Stokes et al 1971). Frangou (2005) provides an up to date review on current treatment options in bipolar depression highlighting encouraging results with a mood stabiliser called lamotrogine.

ELECTROCONVULSIVE THERAPY/TRANSCRANIAL MAGNETIC STIMULATION

DEPRESSION

ECT has been shown to be effective in the treatment of severe and treatment resistant depression (UK ECT Review Group, 2003). The mode of action is still unclear however various hypotheses have been postulated (Bajbouj et al, 2005; Royal College of Psychiatrists, 2005). These include modulation of the brain monoamine systems and increased expression of a neuroprotective protein, brain-derived neurotrophic factor (BDNF), which antagonises the neurotoxic effects of stress on the brain.

Repetitive transcranial magnetic stimulation is another physical treatment that has been subjected to scientific evaluation. A recent systematic review shows superior efficacy against sham treatment after two weeks but this effect is not maintained (Martin et al 2003). As the included trials within this systematic review were of low quality further randomised trials are required. Other physical treatments for treatment resistant depression include vagus nerve stimulation however current evidence is low quality and the side effect profile appears concerning (Corcoran, 2006).

BIPOLAR AFFECTIVE DISORDER

For depressive relapses ECT has similar indications with evidence as listed above. Manic presentations have also been empirically studied. The Royal College of Psychiatrists consensus group have recommended the use of ECT ‘for severe mania associated with life-threatening physical exhaustion or treatment resistance.’ (Royal College of Psychiatrists, 2005).

PSYCHOLOGICAL TREATMENTS

DEPRESSION

Psychotherapy is a broad definition for ‘talking therapies’ that have been used to help people who suffer psychological problems. These can be delivered either via a computer, self help manual, group format or through individual one on one sessions. Many practitioners use an eclectic mix of techniques (psychodynamic, cognitive behavioural, interpersonal, cognitive analytical and dialectal behavioural to name a few). It is the cognitive behavioural model (Beck et al 1979) that has been subjected to the most rigorous research and is included in the NICE guidelines as an initial treatment for mild to moderate depression or as an augmentation strategy for treatment resistant cases. Recent governmental funding for this mode of treatment (British Broadcasting Corporation, 2007) has resulted in a huge increase in CBT being delivered in primary care. It is unclear exactly how CBT effects change in people with depression however a key component of the therapy is encouraging the patient to learn to recognise their negative thinking patterns and how to re-evaluate their thinking. This approach also requires people to practise this by completing ‘homework’ tasks between sessions.

It is beyond the scope of this essay to look at the evidence base for other psychological therapies however a key difficulty in developing a robust psychodynamic psychotherapy trial is ensuring fidelity to the model. In practice, the use of free association and eclectic practice styles poses methodological problems. Regardless of model Frank et al (1991) has delineated a number of common factors that bring all these models together and are thought to underpin the usefulness of these therapies. Examples of these factors include the development of a therapeutic alliance, an opportunity to vent distress, the acquisition and practice of new behaviours, positive therapeutic expectations, positive qualities possessed by the therapist and a plausible means for resolving an individuals psychological problems.

BIPOLAR AFFECTIVE DISORDER

CBT has been studied for use in bipolar affective disorder to reduce the incidence of illness recurrence (Scott et al 2006) and improve psychosocial functioning and treatment adherence (Patelis-Siotis et al 2001). The main focus for CBT in bipolar disorder is on compliance to treatment and sees CBT as an additional treatment strategy to synergistically improve outcome.

SOCIAL INTERVENTIONS

DEPRESSION

The use of ‘ecotherapy’ in the treatment of depression has prompted many physicians to prescribe daily exercise (Biddle et al 1994). Just how exercise helps depression is not known, however, a number of ideas have been proposed. Exercise may distract negative thoughts and the ability to master a new skill may improve self-esteem and self-worth (Lepore, 1997; Mynors-Wallis et al 2000). The physiological effects of exercise may also lead to changes in endogenous endorphin and monoamine levels (Leith, 1994; Thoren et al 1990).

A study by Brown and Harris (1978) illustrated the role of social support in the pathogenesis of depression. The NICE guidelines looked at a randomised control trial investigating the efficacy of ‘befriending’ in depressed subjects (Harris et al 1999). There is some evidence that this social support can increase chances of patients achieving remission and many non government organisations offer befriending to at risk client groups.

BIPOLAR AFFECTIVE DISORDER

Good quality social support in patients with bipolar affective disorder has been shown to improve outcome, reduce compulsory admissions and diminish suicidal ideation (Johnson et al 1999; Johnson et al 2000; Johnson et al 2003, Cohen et al 2004, Webber and Huxley, 2004, Sokero et al 2003, Dennis et al 2005). NICE (2006) have also recommended befriending as a treatment in addition to pharmacological and psychological treatments based on the evidence indicated above for depression.

OTHER TREATMENTS

LIGHT THERAPY

The use of a specialised light box each day has been shown to be as efficacious as antidepressant therapy for treatment of nonseasonal depression (Golden et al, 2005). Its mode of action is poorly understood, however, melatonin is thought to be depressogenic and its release is inhibited during daylight. The light box has also had promising results with seasonal affective disorder, an affective illness where a patient’s mood follows a meterological rhythm dependent on the time of year. There were limitations to this study and further replication is required.

ACUPUNCTURE

Cochrane have released a review on poor quality studies that do not recommend acupuncture for the treatment of depression (Smith et al, 2005).

MUSIC THERAPY

Cochrane have also published a review on the efficacy of music therapy in the treatment of depression (Maratos et al 2008). Given the paucity of studies and the inability to meta analyse results the authors report the need for further studies in this area.

PHARMACOTHERAPY

A number of new pharmacological agents have been researched. Oxcarbazepine (Vasudev et al 2008), Modafinil (Frye et al 2007), and pramipexole (Whiskey et al 2004) show promise in treating the cognitive deterioration related to bipolar depression. Use of fish oils as an adjunctive therapy showed promising results initially however these results have not been replicated (Stoll et al 1999).

CONCLUSION

Mood disorders are common and are associated with significant physical and psychological morbidity. Although the use of current psychotropic medication has had an impact on treating patients with mood disorders only 21-42% of patients who enter treatment achieve full remission (Fawcett, 1994). With the advent of safer pharmacological agents it is now evident research needs to be targeted at generating more efficacious agents to achieve greater remission for partial responders. Given that more than 80% of patients with mood disorders are managed only in primary care it is necessary for service planners and commissioners to appropriate funds accordingly to allow those patients with unmet needs to be effectively diagnosed and given timely interventions to aid recovery.

REFERENCES

Ackenheil M (2001) Neurotransmitters and signal transduction processes in bipolar affective disorders: a synopsis. Journal of Affective Disorders. 62, 101-111.

American Psychiatric Association. (2000). Diagnostic and statistical manual of mental disorders (Revised 4th ed.). Washington, DC: Author.

Angst J, and Stabl M. (1992). Efficacy of moclobemide in different patient groups: a meta-analysis of studies. Psychopharmacology, 106, S109–13.

Bajbouj M, Luborzewski A, Danker-Hopfe H. and Lang U. (2005) Motor Cortical Excitability in Depressive Patients After Electroconvulsive Therapy and Repetitive Transcranial Magnetic Stimulation. Journal of ECT, 21(4),243-245.

Bauer M and Döpfmer S. (1999) Lithium augmentation in treatment-resistant depression: meta-analysis of placebo-controlled studies. Journal of Clinical Psychopharmacology. 19, 427–34.

Beck A.T, Rush A.J., Shaw B. F., and Emery, G. (1979). Cognitive therapy of depression. New York: Guilford.

Biddle S, Fox K. and Edmund L. (1994). Physical Activity in Primary Care in England. London: Health Education Authority.

British Broadcasting Corporation (2007) More funds for talking therapies. See: http://news.bbc.co.uk/1/hi/health/7037400.stm 25th February 2008.

Brown G. and Harris T. (1978). The Social Origins of Depression: A Study of Psychiatric Disorder in Women. London: Tavistock Publications.

Calabrese J. R., Bowden C.L., Sachs G. S., Ascher J.A., Monaghan E, Rudd G.D. (1999). A double-blind placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar depression. Journal of Clinical Psychiatry. 60, 79-88.

Cohen A.N., Hammen C. and Henry R.M. (2004) Effects of stress and social
support on recurrence in bipolar disorder. Journal of Affective Disorders, 82,
143–147.

Cooper B (2001) Nature, nurture and mental disorder: old concepts in the new millennium. British Journal of Psychiatry Supplement. 40, s91-101.

Corcoran, C (2006) Vagus nerve stimulation in chronic treatment-resistant depression. The British Journal of Psychiatry, 189, 282-283.

Curtin F. and Schulz P. (2004).Clonazepam and lorazepam in acute mania: a Bayesian meta-analysis. Journal of Affective Disorders, 78(3), 201-208.

Dennis M, Wakefield P. and Molloy C. (2005) Self-harm in older people with
depression: comparison of social factors, life events and symptoms. British
Journal of Psychiatry, 186, 538–539.

Falret J. (1854) Memoire sur la folie circulaire. Bulletin de la Academie Imperiale de Medicin (Paris), 19, 382–400.

Fawcett J. (1994) Overview of mood disorders: diagnosis, classification, and management. Clinical Chemistry, 40(2):273-8.

Frangou S. (2005) Advancing the pharmacological treatment of bipolar depression. Advances in Psychiatric Treatment, 11, 28–37.

Frank J. D. and Frank J. B. (1991). Persuasion and healing: A comparative study of psychotherapy (3rd ed.). Baltimore, MD: Johns Hopkins University.

Freud S. (1957) Mourning and melancholia. In Standard edition of the complete psychological works of Sigmund Freud, Vol. 14 (ed. J. Strachey), pp. 243–58. Hogarth Press, London, 1957.

Frye M, Grunze H, Suppes T, McElroy S.L., Keck P. E., Walden J, Leverich G.S., Altshuler L.L., Nakelsky S, Hwang S, Mintz J. and Post R.M. (2007) A Placebo-Controlled Evaluation of Adjunctive Modafinil in the Treatment of Bipolar Depression American Journal of Psychiatry, 164, 1242 - 1249.

Golden R.N., Gaynes B.N. and Ekstrom R.D. (2005) The efficacy of light therapy in the treatment of mood disorders: a review and meta-analysis of the evidence. American Journal of Psychiatry. 162, 656-662.

Goodwin G.M. (2003) Evidence-based guidelines for treating Bipolar Disorder: recommendations from The British Association for Psychopharmacology. Journal of Psychopharmacology, 17, 149-173.

Harris T, Brown G.W., and Robinson R. (1999) Befriending as an intervention for chronic depression among women in an inner city: Randomised controlled trial. British Journal of Psychiatry, 174, 219–224.

Jackson S. (1986) Melancholia and depression: from Hippocratic times to modern times. Yale University Press, New Haven, CT.

Johnson, S.L., Winett, C.A. and Meyer, B. (1999) Social support and the course of bipolar disorder. Journal of Abnormal Psychology, 108, 558–566.

Johnson S.L., Meyer B. and Winett C.A. (2000) Social support and self-esteem predict changes in bipolar depression but not mania. Journal of Abnormal Psychology, 108, 558–566.

Johnson L, Lundstrom O. and Aberg-Wistedt A. (2003) Social support in
bipolar disorder: its relevance to remission and relapse. Bipolar Disorders, 5,
129–137.

Kirsch I. and Sapirstein G. (1998) Listening to Prozac but hearing placebo: a meta-analysis of antidepressant medication. Prevention & Treatment, 1, Article 2. http://www.journals.apa.org/prevention/volume1/pre0010002a.html 6th March 2008.

Kirsch I, Deacon B.J., Huedo-Medina T.B., Scoboria A and Moore T.J. (2008) Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration. PLoS Med 5(2): e45 doi:10.1371/journal.pmed.0050045.

Leith L.M. (1994). Foundations of Exercise and Mental Health (pp.17–44). Morgantown, WV:Fitness Information Technology.

Lepore S.J. (1997). Expressive writing moderates the relation between intrusive thoughts and depressive symptoms. Journal of Personality and Social Psychology, 73(5), 1030–1037.

Linde K, Mulrow C.D., Berner M and Egger M. (1998) St John's Wort for depression. Cochrane Database of Systematic Reviews, Issue 4.

Maratos A.S., Gold C, Wang X. and Crawford M.J. (2008) Music therapy for depression. Cochrane Database of Systematic Reviews, Issue 1.

Martin J. L. R., Barbanoj M. J. and Schlaepfer T. E. (2003) Repetitive transcranial magnetic stimulation for the treatment of depression: systematic review and meta-analysis. British Journal of Psychiatry, 182, 480 –491.

McAskill R, Mir S, Taylor D. (1998) Pindolol augmentation of antidepressant therapy. British Journal of Psychiatry,173, 203-8.

Morris J.B. and Beck, A.T. (1974) The efficacy of antidepressant drugs: a review of research. Archives of General Psychiatry, 30, 667–74.

Mynors-Wallis L.M., Gath D.H. and Baker F. (2000) Randomised controlled trial of problem-solving treatment, antidepressant medication, and combined treatment for major depression in primary care. British Medical Journal, 320(7226), 26–30.

NICE (2004) Depression:Management of depression in primary and secondary care. National Clinical Practice Guideline Number 23, National Institute for Health and Clinical Excellence.

NICE (2006) The management of bipolar disorder in adults, children and adolescents, in primary and secondary care. National Clinical Practice Guideline Number 38, National Institute for Health and Clinical Excellence.

Nirenberg A.A., Feighner J.P. and Rudolph R. (1994) Venlafazine for treatment-resistant unipolar depression. Journal of Clinical Psychopharmacology, 14, 419-423.

Patelis-Siotis I, Young T, Robb J, Marriott M, Bieling P, Cox L. and Joffe R. (2001) Group cognitive behavioural therapy for bipolar disorder: a feasibility and effectiveness study, Journal of Affective Disorders, 65(2), 145-153.

Peet M. (1994) Induction of mania with selective serotonin re-uptake inhibitors and tricyclic antidepressants. British Journal of Psychiatry, 164, 549–550.

Royal College of Psychiatrists (2005) The ECT Handbook (Second edition): The Third Report of the Royal College of Psychiatrists’ Special Committee on ECT.

Scott J, Paykel E, Morriss R. Bentall R, Kinderman P, Johnson T, Abbott R. and Hayhurst H. (2006) Cognitive–behavioural therapy for severe and recurrent bipolar disorders. Randomised controlled trial. British Journal of Psychiatry, 188, 313 –320.

Smith C. A. and Hay P.P.J. (2005) Acupuncture for depression. Cochrane Database of Systematic Reviews, Issue 2.

Sokero T.P., Melartin T.K. and Rytsala H.J. (2003) Suicidal ideation and attempts among psychiatric patients with major depressive disorder. Journal of Clinical Psychiatry, 64, 1094–1100.

Song F, Freemantle N. and Sheldon T.A. (1993). Selective serotonin reuptake inhibitors: meta-analysis of efficacy and acceptability. British Medical Journal, 306, 683–7.

Stokes P. E., Shamoian C. A. and Stoll P. M. (1971) Efficacy of lithium as acute treatment of manic–depressive illness. Lancet, 1, 319–325.

Stoll A. L., Severus E, Freeman M. P., Stephanie Rueter S, Zboyan H. A., Diamond E, Cress K.K. and Marangell L.B. (1999). Omega 3 fatty acids in bipolar disorder. A preliminary double-blind, placebo-controlled trial. Archives of General Psychiatry, 56 (5), 407-412.

Taylor D, Kerwin R. and Paton C. (2007) The Maudsley 2007-2008 prescribing guidelines. 9th edn. London: Taylor & Francis.

Thoren P., Floras J.S. and Hoffmann P. (1990). Endorphins and exercise: Physiological mechanisms and clinical implications. Medical Science, Sports and Exercise, 22(4), 417–428.

UK ECT Review Group (2003) Efficacy and safety of electroconvulsive therapy in depressive disorders: a systematic review and meta-analysis. Lancet, 361, 799 –808.

van Praag H. and Korf J. (1971) Endogenous Depression With and Without Disturbance of 5-Hydrxytryptamine Metabolism: A Biochemical Classification? Psychopharmacology, 19,148-152.

Vasudev A, Macritchie K, Watson S, Geddes J.R. and Young A.H. (2008) Oxcarbazepine in the maintenance treatment of bipolar disorder. Cochrane Database of Systematic Reviews, Issue 1.

Webber M. and Huxley P. (2004) Social exclusion and risk of emergency compulsory admission. A case-control study. Social Psychiatry and Psychiatric Epidemiology, 39, 1000–1009.

Whiskey E. and Taylor D. (2004) Pramipexole in unipolar and bipolar depression Psychiatric Bulletin, 28, 438-440.


World Health Organization (1992-1994). International Statistical Classification of Diseases and Related Health Problems; Tenth Revision, Volumes 1 to 3. Geneva: World Health Organization.


Young S. N. (1991) Use of tryptophan in combination with other antidepressant treatments: a review. Journal of Psychiatry and Neuroscience, 16(5), 241-6.

 

Copyright Priory Lodge Education Limited 1994-2008
First Published Septmber 208
Home • Journals • Search • Rules for Authors • Submit a Paper • Sponsor us   
priory.com
Home
Journals
Search
Rules for Authors
Submit a Paper
Sponsor Us

Google Search


Advanced Search

 


 

Default text | Increase text size