Managing Major Depressive Disorder in Primary Care – Lundbeck Limited

Brintellix® (vortioxetine) film-coated tablets

Prescribing information: Please refer to the full Summary of Product Characteristics (SPC) before prescribing, particularly in relation to side effects, precautions and contraindications Presentation: Tablets containing 5, 10 or 20mg of vortioxetine (as the hydrobromide). Indications: Treatment of major depressive episodes in adults. Dosage: 10mg once daily. Dose may be increased to a maximum of 20mg daily or reduced to 5mg if necessary. After depressive symptoms resolve, treatment for at least 6 months is recommended. Elderly (≥65 years): Initial dosage is 5mg once daily. Caution advised if using doses above 10mg daily as data are limited. Children and adolescents (<18 years): Not recommended as safety and efficacy not established. Cytochrome P450 inhibitors and inducers: Consider a dose reduction of vortioxetine if a strong CYP2D6 inhibitor is added. Consider a dose adjustment if a broad CYP450 inducer is added to treatment. Renal impairment: Exercise caution in severe impairment as data are limited in these patients. Hepatic impairment: Exercise caution in severe hepatic impairment as no data in these patients. Contraindications: Hypersensitivity to the active substance or any of the excipients. Concomitant use with non-selective, monoamine oxidase inhibitors (MAOIs) or selective MAO-A inhibitors (e.g. moclobemide). Fertility, pregnancy and lactation: Do not use in pregnancy unless clinically necessary. Limited data on the use of vortioxetine in pregnant women. Animal studies have shown reproductive toxicity. Use of SSRIs in pregnancy, particularly in late pregnancy, may increase the risk of persistent pulmonary hypertension in the newborn (PPHN). It is expected that vortioxetine will be excreted into human milk, and a risk to the suckling child cannot be excluded. Fertility: Animal data showed no effect on fertility, sperm quality or mating performance. Human case reports with some SSRIs have shown that an effect on sperm quality is reversible. Impact on human fertility has not been observed so far. Precautions: Use caution when driving a car or operating machinery. Closely supervise patients, especially those at high risk, for suicide-related behaviours during first few weeks of treatment and during dose changes. Use with caution in patients: at risk of hyponatraemia; with a history of mania/hypomania; undergoing ECT; with unstable epilepsy (discontinue if seizures begin for the first time or increase in frequency); with bleeding tendencies/ disorders, taking anticoagulants or medicines affecting platelet function; in patients on lithium or tryptophan. Monitor patients for appearance of serotonin syndrome or neuroleptic malignant syndrome, and discontinue if occurs. Drug interactions: Alcoholic drinks not advisable. Vortioxetine is extensively metabolised in the liver, primarily through oxidation catalysed by

CYP2D6 and to a minor extent CYP3A4/5 and CYP2C9. Potential for interactions with: MAOIs, MAO-A and MAO-B inhibitors; serotonergic medicines (e.g. triptans or tramadol); St John’s wort; products which may lower the seizure threshold, e.g. antidepressants (tricyclic, SSRIs, SNRIs), neuroleptics (phenothiazines, thioxanthenes and butyrophenones), mefloquine or bupropion. Depending on individual patient response, a lower dose of vortioxetine may be considered if strong CYP2D6 inhibitor (e.g. bupropion, quinidine, fluoxetine, paroxetine) is added to vortioxetine treatment. Additionally these effects may be greater in patients who are poor metabolisers of CYP2D6. A dose adjustment may be considered if a broad cytochrome P450 inducer (e.g. rifampicin, carbamazepine, phenytoin) is added to vortioxetine treatment. Adverse events: Adverse reactions were usually mild or moderate, transient and occurred within the first two weeks of treatment. The following adverse events were reported: Very common (>1/10 patients); nausea. Common (>1/100 <1/10); abnormal dreams, dizziness, diarrhoea, constipation, vomiting, pruritis, including generalised pruritis. Uncommon (>1,000 <1/100); flushing, night sweats. Unknown: Serotonin syndrome. Sexual dysfunction: The 20mg dose of vortioxetine was associated with an increase in treatment-emergent sexual dysfunction. Class effect: Studies in patients ≥50 years of age, show an increased risk of bone fractures in patients receiving SSRIs and TCAs. Not known if relevant to vortioxetine. Prescribers should consult the full SPC in relation to other side effects. Overdose: Limited experience. Management consisting of treating clinical symptoms and relevant monitoring. Legal category: POM. Brintellix Tablets, blisters of: 5mg (EU/1/13/891/002)

28 tablets, £27.72; 10mg (EU/1/13/891/010)

28 tablets, £27.72; 20mg (EU/1/13/891/028) 28 tablets, £27.72. Further information available from: Lundbeck Limited, Building K1, Timbold Drive, Kents Hill, Milton Keynes, MK7 6BZ. Tel: 01908 638972.

® Brintellix is a Registered Trade Mark.

Date of last revision of PI: June 2015

Job number: UK/VOR/1509/0150c

Date of preparation: March 2016

References

1. Brintellix Summary of Product Characteristics.

2. NICE Technology Appraisal 367. November 2015. nice.org.uk/guidance/ta367.

Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard. Adverse events should also be reported to Lundbeck Limited, Medical Information, on: 01908 638972.

The clinical effectiveness of Brintellix® (vortioxetine) for cognitive function improvement in patients with

major depressive disorder

Major depressive disorder (MDD) is a leading cause of disability and disease burden.1 It is a complex multidimensional and heterogeneous disorder characterised by a wide range of emotional, physical and cognitive symptoms (see figure 1).2-4 The new generation antidepressant vortioxetine effectively addresses the emotional, physical and cognitive symptoms of depression, and is the first depression treatment to have information about its effect on cognition included in the SmPC.5

Among patients with depression, there is a high failure rate for commonly-used antidepressant treatments due to a lack of efficacy, residual symptoms, tolerability or inadequate adherence.6-8 Providing physicians with a choice of effective, well-tolerated treatments allows patients the best chance of recovery.

Emotional symptoms2 Cognitive symptoms2-4

Difficulties with:

Attention and concentration

Short- and long-term memory

Decision making

The results of the survey are supported by clinical evidence that suggests cognitive symptoms are present for around 94% of time during an episode of depression, and 44% of time between episodes (see graph 1).11 These cognitive symptoms can adversely affect life functioning, independent of improvement in depressive symptoms.9

Lack of enjoyment

Suicidal ideation

Hopelessness

Inappropriate guilt

Planning and organisation

Mental sharpness

Word-finding

Thinking speed Judgement

Fatigue

Eating/weight changes

Joint, abdominal, and other pains

Insomnia/hypersomnia

Sexual dysfunction

Headaches

Psychomotor agitation

Physical symptoms2

Cognition is an unmet treatment need in depression

Cognitive impairment is associated with life-functioning disability affecting a range of cognitive domains including attention, working memory, verbal and non-verbal learning, motor and executive function.9 According to a survey of 200 British adults diagnosed with depression, almost all patients believed they had experienced at least one symptom of cognitive dysfunction during an episode of depression (see figure 2).10

Graph 1: Presence of residual symptoms during major depressive episodes and non-major depressive episodes in 267 depressed primary care patients11

Current treatments do not address cognitive dysfunction

Current treatments, including SSRIs (selective serotonin reuptake inhibitors) and SNRIs (serotonin-norepinephrine reuptake inhibitors) have limited data for impact on depression-related cognitive dysfunction.12,13 A recent study investigating the effect of three antidepressant drugs (escitalopram, sertraline, venlafaxine extendedrelease) on five cognitive domains showed no relative improvement, even in those patients achieving clinical remission. Broader cognitive impairment was associated with greater illness chronicity (earlier illness onset) but not with symptom severity or previous antidepressant failures.14

Vortioxetine addresses both mood and cognitive symptoms

Vortioxetine is a new generation antidepressant, licensed for the treatment of major depressive episodes (MDE) in adults. Its novel mode of action offers an alternative treatment option for effectively addressing both the mood and cognitive symptoms of depression in a range of patients.5

Following European Medicines Agency approval,15 the National Institute for Health & Care Excellence (NICE) recommended vortioxetine as a clinically- and cost-effective treatment option for patients with MDE who have not adequately responded to two other antidepressants within the current episode.16 This was the first positive Technology Appraisal that NICE had completed for an antidepressant, providing a welcome additional treatment option for patients with MDE in whom previous treatments were suboptimal or caused intolerable side-effects.

Mode

action

Unlike selective serotonin SSRIs and SNRIs, which work via only one action (blocking neurotransmitter reuptake), vortioxetine has a multimodal action, modulating serotonergic receptor activity and reuptake inhibition. Pre-clinical studies show it modulates several neurotransmitter systems.17

Figure 1: Depression is a clinically heterogeneous disorder2-4

Figure 2: Depression patients’ experience of cognitive dysfunction. Results from a 2015 survey of 200 British adults diagnosed with depression10

Efficacy in a range of patients

Vortioxetine has demonstrated broad antidepressant efficacy in:

• Severe depression (MADRS ≥30)18

• Depression with high concomitant anxiety (HAM-A ≥20)19

• Elderly patients (≥65 years)20

• Prevention of relapse of depression21

• Depressed patients with a suboptimal response to an initial SSRI or SNRI22

• Maintenance of effect over 12 months of treatment23

Efficacy in depression-related cognitive dysfunction

Vortioxetine is the only licensed treatment that has been shown to consistently improve both the mood and cognitive symptoms of depression.2 Analysis of three separate studies indicated that vortioxetine 5mg, 10mg, and 20mg has a direct effect on cognitive performance (as measured by the Digit Symbol Substitution Test) in addition to an indirect effect elicited by the improvement in general depressive symptoms, after 8 weeks of treatment.20,24,25

The FOCUS study found a positive effect on cognitive performance was observed for 10mg and 20mg doses of vortioxetine after correction for the alleviation of depressive symptoms.24 The proportions of direct effect were 64% and 48% for vortioxetine 10mg and 20mg respectively for the composite z-score, and 66% and 56% respectively for the Digit Symbol Substitution Test score.24

The CONNECT study showed vortioxetine treatment significantly improved everyday functioning in patients with depression, including household chores, communication, finance, transportation and planning/recreational activities, compared with placebo.25

Elderly patients (≥65 years) receiving vortioxetine 5mg per day achieved significantly greater improvement in cognitive performance measures compared with placebo (P<0.05).20 This was a pre-specified secondary endpoint.20

In addition, following 8–12 weeks of treatment, vortioxetine significantly improved partner and family interactions and quality of relationships, as assessed by the Depression and Family Functioning Scale.26

Tolerability

Vortioxetine is generally well tolerated, with low discontinuation rates due to adverse events.5 The most common adverse event seen in clinical trials was nausea, which was generally mild or moderate in severity and transient.5

Vortioxetine offers an effective alternative treatment option for physicians and their patients that has been shown to consistently improve the mood, cognitive and physical symptoms of depression.

For further information about depression please visit www.unlockdepression.co.uk and for additional information about vortioxetine please visit www.brintellix.co.uk

Lundbeck Medical Information can be contacted on: +44 (0)1908 638972 or via email: ukinfo@lundbeck.com. Please consult the vortioxetine Summary of Product Characteristics before prescribing (www.medicines.org.uk/emc).

1. Ferrari AJ et al. PLOS Medicine 2013; 10: 11 e1001547. 2. APA. DSM-5. 2013. 3. Marazziti et al. Eur J Pharmacol 2010; 626(1): 83–86. 4. Hammar & Ardal. Front Hum Neurosci 2009; 3: 26. 5. Brintellix®. Summary of Product Characteristics (SmPC). 6. Shelton RC. Primary Psychiatry 2006; 13(4): 73–82. 7. Trivedi MH et al. Am J Psych 2006; 163(1): 28–40. 8. Kelly K et al. Dialogues Clin Neurosci 2008; 10(4): 409–418. 9. Jaeger J et al. Psychiatry Res 2006; 145:39–48. 10. ComRes Exploring cognitive dysfunction in people with depression, Survey commissioned and funded by Lundbeck Ltd in collaboration with Depression Alliance; Jul 2015. 11. Conradi et al. Psychol Med 2011; 41(6): 1165–1174. 12. Reppermund S et al. Psychol Med 2009; 39: 603–614. 13. Weiland-Fiedler P et al. J Affect Disord 2004; 82: 253–258. 14. Shilyansky C et al. The Lancet Psychiatry 2016; DOI: http://dx.doi.org/10.1016/S22150366(16)00012-2, 15. European Medicines Agency (EMA) Committee for Medicinal Products for Human Use (CHMP); 24 Oct 2013. 16. Final appraisal determination: Vortioxetine for treating major depressive episodes. NICE ID583; Oct 2015. 17. Sanchez C et al. Pharmacol Ther 2015; 145: 43–57. 18. Alvarez E et al. Int J Neuropsychopharmacol 2012; 15: 589–600, 19. Boulenger JP et al. Int Clin Psychopharmacol 2014; 29: 138–149. 20. Katona C et al. Int Clin Psychopharmacol 2012; 27: 215–212. 21. Boulenger JP et al. J Psychopharmacol 2012; 26: 1408–1416. 22. Montgomery SA et al. Hum Psychopharmacol 2014; 29(5): 470–482. 23. Baldwin DS et al. Curr Med Res Opin 2012; 28: 1717–1724. 24. McIntyre RS et al. Int J Neuropsychopharmacol 2014; 17 (10): 1557–1567. 25. Mahableshwarkar AR, et al. Neuropsychopharmacol 2015; 40 (8): 2025–2037. 26. François C et al. Poster PMH52 presented at the 20th ISPOR Annual International Meeting, Philadelphia, Pennsylvania, USA. 16–20 May, 2015.

Brintellix® (vortioxetine) film-coated tablets

Prescribing information: Please refer to the full Summary of Product Characteristics (SPC) before prescribing, particularly in relation to side effects, precautions and contraindications. Presentation: Tablets containing 5, 10 or 20mg of vortioxetine (as the hydrobromide Indications: Treatment of major depressive episodes in adults. Dosage: 10mg once daily. Dose may be increased to a maximum of 20mg daily or reduced to 5mg if necessary. After depressive symptoms resolve, treatment for at least 6 months is recommended. Elderly (≥65 years): Initial dosage is 5mg once daily. Caution advised if using doses above 10mg daily as data are limited. Children and adolescents (<18 years): Not recommended as safety and efficacy not established. Cytochrome P450 inhibitors and inducers: Consider a dose reduction of vortioxetine if a strong CYP2D6 inhibitor is added. Consider a dose adjustment if a broad CYP450 inducer is added to treatment. Renal impairment: Exercise caution in severe impairment as data are limited in these patients. Hepatic impairment: Exercise caution in severe hepatic impairment as no data in these patients. Contraindications: Hypersensitivity to the active substance or any of the excipients. Concomitant use with non-selective, monoamine oxidase inhibitors (MAOIs) or selective MAO-A inhibitors (e.g. moclobemide). Fertility, pregnancy and lactation: Do not use in pregnancy unless clinically necessary. Limited data on the use of vortioxetine in pregnant women. Animal studies have shown reproductive toxicity. Use of SSRIs in pregnancy, particularly in late pregnancy, may increase the risk of persistent pulmonary hypertension in the newborn (PPHN). It is expected that vortioxetine will be excreted into human milk, and a risk to the suckling child cannot be excluded. Fertility: Animal data showed no effect on fertility, sperm quality or mating performance. Human case reports with some SSRIs have shown that an effect on sperm quality is reversible. Impact on human fertility has not been observed so far. Precautions: Use caution when driving a car or operating machinery. Closely supervise patients, especially those at high risk, for suicide-related behaviours during first few weeks of treatment and during dose changes. Use with caution in patients: at risk of hyponatraemia; with a history of mania/ hypomania; undergoing ECT; with unstable epilepsy (discontinue if seizures begin for the first time or increase in frequency); with bleeding tendencies/disorders, taking anticoagulants or medicines affecting platelet function; in patients on lithium or tryptophan. Monitor patients for appearance of serotonin syndrome or neuroleptic malignant syndrome, and discontinue if occurs. Drug interactions: Alcoholic drinks not advisable. Vortioxetine is extensively metabolised in the liver, primarily through oxidation catalysed by CYP2D6 and to a minor extent CYP3A4/5 and CYP2C9. Potential for interactions with: MAOIs, MAO-A and MAO-B inhibitors; serotonergic medicines (e.g. triptans or tramadol); St John’s wort; products which may lower the seizure threshold, e.g. antidepressants (tricyclic, SSRIs, SNRIs), neuroleptics (phenothiazines, thioxanthenes and butyrophenones), mefloquine or bupropion. Depending on

individual patient response, a lower dose of vortioxetine may be considered if strong CYP2D6 inhibitor (e.g. bupropion, quinidine, fluoxetine, paroxetine) is added to vortioxetine treatment. Additionally these effects may be greater in patients who are poor metabolisers of CYP2D6. A dose adjustment may be considered if a broad cytochrome P450 inducer (e.g. rifampicin, carbamazepine, phenytoin) is added to vortioxetine treatment. Adverse events: Adverse reactions were usually mild or moderate, transient and occurred within the first two weeks of treatment. The following adverse events were reported: Very common (≥1/10 patients); nausea. Common (≥1/100 <1/10); abnormal dreams, dizziness, diarrhoea, constipation, vomiting, pruritis, including generalised pruritis. Uncommon (≥1,000 <1/100); flushing, night sweats. Unknown: Serotonin syndrome. Sexual dysfunction: The 20mg dose of vortioxetine was associated with an increase in treatment-emergent sexual dysfunction. Class effect: Studies in patients ≥50 years of age, show an increased risk of bone fractures in patients receiving SSRIs and TCAs. Not known if relevant to vortioxetine. Prescribers should consult the full SPC in relation to other side effects. Overdose: Limited experience. Management consisting of treating clinical symptoms and relevant monitoring. Legal category: POM. Brintellix Tablets, blisters of: 5mg (EU/1/13/891/002) 28 tablets, £27.72; 10mg (EU/1/13/891/010) 28 tablets, £27.72; 20mg (EU/1/13/891/028) 28 tablets,£27.72. Further information available from: Lundbeck Limited, Building K1, Timbold Drive, Kents Hill, Milton Keynes, MK7 6BZ. Tel: 01908 638972.

®Brintellix is a Registered Trade Mark.

Date of last revision of PI: June 2015

Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard.

Adverse events should also be reported to Lundbeck Limited, Medical Information, on: 01908 638972

Job number: UK/VOR/1603/0283

Date of preparation: May 2016

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Foreword

Major depressive disorder is relatively common, affecting an estimated 5% to 10% of people seen in primary care, 10% to 14% of medical inpatients and up to 15% of older people1

DEPRESSION

IS a common, chronic, underfunded2, major impact disease that affects personal life, social life, family life, relationships, work and business. The World Health Organisation (WHO) has estimated that depression and anxiety disorders costs the global economy more than $1 trillion dollars per year3 and that more than 350 million people4 are affected (it estimates that only 10% are receiving effective treatment). In 2010 the cost of depression to the EU was estimated as 92 million Euros5. The UK Royal College of Psychiatrists recognises the significant disease burden of depression and other mental health disorders6

Depression can affect all age groups and has ranges of severity. It can be alone or part of a cyclic mania/ hypomania syndrome or it may be associated with other mental and physical health co-morbidities. The symptoms of depression are well illustrated by the following videos:

1) https://www.youtube.com/watch?v=XiCrniLQGYc7

2) http://www.rcpsych.ac.uk/healthadvice/problemsdisorders/depression.aspx8

The milder versions of depression may be amenable to talking therapies, exercise and social support but once the disease is severe, medication and/or new technologies are needed. Traditional medication for pure depression can improve mood but is not a cure. Until recently no depression medication was proven to be effective at managing the cognitive deficits associated with major depression. Fortunately, this situation has changed with the introduction of Vortioxetine (Brintellex). NICE recommends this medication in the following conditions8:

Vortioxetine is recommended as an option for treating major depressive episodes in adults whose condition has responded inadequately to 2 antidepressants within the current episode9

The General Practitioner keen to help their severely depressed patient function better or even possibly get back to work faster would be wise to consider this medication.

Dr Charles Easmon Editor

Dr Charles Easmon is a medical doctor with 30 years’ experience in the public and private sectors. After qualifying as a physician, he developed his interests in occupational medicine, public health and travel diseases

References:

1 https://www.nice.org.uk/news/press-and-media/nice-draft-guidance-recommends-vortioxetine-brintellix-for-treating-major-depressiveepisodes Accessed 22/4/2016

2 http://www.who.int/mediacentre/news/releases/2016/depression-anxiety-treatment/en/ Accessed 22/4/2016

3 http://www.who.int/mediacentre/news/en/ Accessed 22/4/2016

4 http://www.who.int/mediacentre/factsheets/fs369/en/ Accessed 22/4/2016

5 https://www.nice.org.uk/news/blog/the-global-crisis-of-depression Accessed 22/4/2016

6 http://www.rcpsych.ac.uk/pdf/Position%20Statement%204%20website.pdf Accessed 22/4/2016

7 https://www.youtube.com/watch?v=XiCrniLQGYc Accessed 22/4/2016

8 https://www.nice.org.uk/guidance/ta367 Accessed 22/4/2016

9 https://www.nice.org.uk/guidance/TA367/chapter/1-Guidance Accessed 22/4/2016

Depression – Overview

Dr Charles Easmon MBBS MRCP MSc Public Health DTM&H DOccMed, Editor

Thus not the tenderness of friendship, nor the beauty of earth, nor of heaven, could redeem my soul from woe: the very accents of love were ineffectual. I was encompassed by a cloud which no beneficial influence could penetrate. The wounded deer dragging its fainting limbs to some untrodden brake, there to gaze upon the arrow which had pierced it, and to die-was but a type of me1.

Mary Shelley quote from Frankenstein, Chapter 9

AT THE age of 19 Mary Shelley, partner/ wife of Shelley and friend of Lord Byron wrote a fantastic description of the flatness of the depressive mood. We recognise in depression a chronic disease with relapses and periods of relative normality. We also recognise an endogenous version, which is part of some people’s chemical and genetic make up as well as a reactive type alongside some who have bi-polar conditions.

The symptoms can be variable and at time incapacitating – a psychotic version of depression is also recognised. The condition is seen as a disorder of mood, thoughts2,3,4, appetites and sleep. Mood is typically flat, thoughts are negative and recurrent with low feelings of self worth, appetites for food, sex and enjoyment are suppressed and sleep is disturbed either as a problem of getting off to sleep or a problem of early morning waking with recurrent negative thoughts5. Sometimes the negative thoughts can lead to suicide or attempted suicide.

Depression: Severity

Depression can vary from mild to very severe and this latter can be a life-threatening psychosis6 NICE recognises the phases as:

1) Persistent sub threshold depressive symptoms or mild to moderate depression7

2) Persistent sub threshold depressive symptoms or mild to moderate depression with inadequate response to initial interventions, and moderate and severe depression in adults8

3) Complex and severe depression in adults9 (although not clearly stated by NICE, as such this seems to equate to Major Depressive Disorder10)

Depression Treatment: Counselling

NICE recommends that the milder phases of depression be treated by counselling without medication. The options for type of counselling are quite wide but the most important factors are

that the counsellor has had appropriate training and has insight into their own skills and limitations. It may be useful for the General Practitioner to remind the patient that they have a choice and that if they do not feel an affinity for a particular counsellor or their course of therapy they should feel free to voice this and, where possible, make changes.

Counselling can be based on changing behaviours that then improve the way people think as well as changing the thoughts directly (classical Cognitive Behavioural Therapy ), which tends to focus on five main areas –situations, thoughts, emotions, physical feelings and actions.

Mindfulness-Based Cognitive Therapy (MBCT) is based on an admixture of cognitive techniques with meditation and awareness12

Dialectical Behaviour Therapy13 can be seen as an offs hoot of Cognitive Behavioural Therapy which has more support and collaboration components and was originally developed for the management of Borderline Personality Disorder.

For some, Group therapy or couples behaviour therapy may be useful.

Depression Treatment: Medication and Innovation

Drugs to manage depression usually act only on the serotonin uptake system and take several weeks to be effective. Most drug treatments manage the condition but do not cure it. Side effects from drugs are common and drug interactions are a significant risk.

Traditional depression drugs that block serotonin reuptake can do so by 2 different mechanisms 1) Selective serotonin reuptake inhibitors (SSRIs) or 2) Serotonin-norepinephrine reuptake inhibitors (SNRIs), These drugs can be seen to be mood-altering but their effect on cognitive dysfunction has shown no relative improvement in a recent study14 (based on

Counselling can be based on changing behaviours that then improve the way people think as well as changing the thoughts directly

five cognitive domains – attention, response inhibition, verbal memory, decision speed, and information processing). This is both important and disappointing. However, a newer drug15 has a multi-modal action, which involves the modulation of several neurotransmitter systems (it blocks neurotransmitter reuptake as well as modulating serotonergic receptor activity and reuptake inhibition). The effect of this multi-modal action is a positive improvement in cognitive dysfunction, which currently makes it unique in this area.

Depression Treatment: Electricity or Magnets

Neurones in the brain communicate by chemical and electrical/magnetic receptors. Electroconvulsive therapy16 (ECT) has been used for many years to treat severe depression but now evidence exists that Transcranial Direct Current stimulation17 (tDCS) may benefit milder cases of depression. Even more exciting is the role of Repetitive Transcranial Magnetic Stimulation18 (rTMS).

Depression and Technology

People interested in mental health and technology have been hard at work. The headspace19 app was developed from a period of meditation

References:

with Buddhist monks who originally thought that the app would never work, Now, it is reported that the Buddhist monks are so impressed that they ask new Buddhist trainee monks to use the app for 6 weeks before they physically join. On-line counselling options are now readily available and in many studies good results have been obtained20

One of the more interesting apps (www.moodscope.com ) involves a clever support mechanism for those with depression. It works by allowing a person with depression to share their mood on a daily basis and the clever bit is that this information is sent securely to a few trusted friends. Those friends can choose to act based on the mood reading and their simple intervention may improve the sufferers quality of life and, in some cases, actually save a life.

Summary

Innovation in depression medication has arrived in the form of a drug that not only acts on serotonin uptake but also on other mechanisms within the brain with a benefit in major depressive illness in that it improves cognitive function.

Non-drug tools such as counselling, electricity, magnets and technology all have a role to play in the successful treatment and management of varying degrees of depression.

1 http://www.pagebypagebooks.com/Mary_Wollstonecraft_Shelley/Frankenstein/Chapter_9_p3.html Accessed 20/4/2016

2 http://tiny.cc/dio2ay Accessed 20/4/2016

3 http://www.ncbi.nlm.nih.gov/pubmed/15488254 Accessed 20/4/2016

4 http://pathways.nice.org.uk/pathways/depression#path=view%3A/pathways/depression/care-for-adults-with-depression.xml&content=view-index Accessed 20/4/2016

5 http://pathways.nice.org.uk/pathways/depression Accessed 20/4/2016

6 http://www.ncbi.nlm.nih.gov/pubmed/24223526 Accessed 20/4/2016

7 http://tiny.cc/iio2ay Accessed 20/4/2016

8 http://tiny.cc/qio2ay Accessed 20/4/2016

9 http://pathways.nice.org.uk/pathways/depression#path=view%3A/pathways/depression/step-4-complex-and-severe-depression-in-adults.xml&content=view-index Accessed 20/4/2016

10 http://www.mentalhealth.com/home/dx/majordepressive.html Accessed 20/4/2016

11 http://www.nhs.uk/Conditions/Cognitive-behavioural-therapy/Pages/Introduction.aspx Accessed 21/4/2016

12 http://mbct.com/ Accessed 21/4/2016

13 http://psychcentral.com/lib/an-overview-of-dialectical-behavior-therapy/ Accessed 21/4/2016

14 http://www.thelancet.com/pdfs/journals/lanpsy/PIIS2215-0366(16)00012-2.pdf Accessed 20/4/2016

15 https://www.nice.org.uk/guidance/ta367/chapter/1-Guidance Accessed 20/4/2016

16 http://pathways.nice.org.uk/pathways/psychosis-and-schizophrenia#content=view-node%3Anodes-psychotic-depression Accessed 21/4/2016

17 http://www.hopkinsmedicine.org/psychiatry/specialty_areas/brain_stimulation/tdcs.html Accessed 21/4/2016

18 https://www.nice.org.uk/guidance/ipg542 Accessed 21/4/2016

19 https://www.headspace.com/register/free-trial?origintoken=google-b&gclid=CIiY1Y_8n8wCFfMW0wodj5sCYA Accessed 21/4/2016

20 http://uk.iesohealth.com/media/1032/ipcress-lancet-article.pdf Accessed 21/4/2016

21 https://www.moodscope.com/ Accessed 21/4/2016

Non-drug tools such as counselling, electricity, magnets and technology all have a role to play in the successful treatment and management of varying degrees of depression

Depression at Work, Sports and in the Arts

Jane Carmichael, Medical Correspondent

WINSTON CHURCHILL1 suffered depression most of his life and called it his ‘black dog’. Interestingly, there was no United Kingdom National Human Resources Manager who said during the Second World War ‘Mr Churchill because of your history of depression we do not regard you as fit to lead the Nation in our war against the Nazis’. Fortunately, despite his depression, Churchill was able to think and make decisions, but sadly many of those with major depressive illness have problems with their ability to think as well as having problems with their mood.

Depression at Work

Depression in the workplace is common and it is vital that, alongside The Equality Act 20102, the General Practitioner (GP) looks for the best ways to manage depression for those in work. They may at times need time away from work or reduce their hours.

The role of the General Practitioner is to take a full health, social and work history and, if this is not possible, consider an early referral to a suitable occupational health practitioner (who may have as long as one hour to make their assessment as opposed to the GP’s maximal 10 minutes).

GPs now issue ‘fit notes3’ instead of ‘sick notes’, but the challenge in depression is to understand whether the altered mood and cognition are suitable to effective working or could work make both worse?

GPs can call on NHS occupational health resources but these are limited and in many cases companies that do not already have inhouse occupational health services, ideally, should ‘buy these’ in.

As Churchill illustrates, those with depression can work but their work and rest need to be well managed. During a severe bout of depression, concentration and decision-making is likely to be poor and during this phase rest is probably the best option. Once mood and/or cognition have improved, a phased return to work can be planned in discussion with the sufferer and ideally with an occupational health professional. The right

work can be therapeutic but, clearly, the wrong, stressful work can be more harmful and finding the balance is not easy. In the simplest terms, if the depression is mild then work modification with supportive counselling may be effective. If the depression is moderate then more work modification and more therapy plus medication is advised but if the depression is severe/(major) then time off work will be needed as the poor cognitive functioning and low mood are not consistent with productive work.

Both the Royal College of Psychiatrists4 and the National Centre for Health and Care Excellence (NICE) recommend counselling supplemented by medication for those with major depressive symptoms. It has been known for some time that traditional serotonin uptake inhibitors can improve but not necessarily cure mood but, most importantly, do not improve cognition. Fortunately a new medication, recommended by NICE, has proven efficacy in improving cognition and this would seem the more logical choice for those who need to return to work and for others who wish to improve the quality of their daily lives.

Depression in Sports

Professional sport is work. It is becoming increasingly recognised that depression affects professional sportsmen at least as commonly as in the general public. Amongst cricketers, recently identified depression sufferers include Marcus Trescothick5 and Freddie Flintoff6. Trescothick has written a very powerful book about his personal experiences with depression and this book is important because, prior to that, it was felt that depression should not be mentioned (when he

The right work can be therapeutic but, clearly, the wrong, stressful work can be more harmful and finding the balance is not easy

had to withdraw from a Pakistan tour, it was reported as due to a gut infection when, in fact, the problem was a recurrence of depression).

Amongst footballers, John Fashanu’s brother, Justin, committed suicide (homophobia and racism probably also had a part to play7).

Whatever the scale of depressive illness in professional sports, one thing is clearimprovements in mood can only be helped by the additional improvements in cognition (even if, as was said of George Best, ‘his brains are in his feet’).

Depression in the Arts

Depression amongst comedians is well recognised and many of our national treasures suffered very badly indeed. Tony Hancock8 committed suicide. Sid James of the Carry On films suffered badly as do Stephen Fry and Ruby Wax.

Ruby Wax 9 has done excellent work on reducing the stigma of depression, extending the discussion and creating a support network for sufferers. Many revelations about entertainers are disclosed in the book by Bruce Dessau, ‘Beyond a Joke; Inside the dark World of Standup Comedy10’.

An apocryphal tale of the great Grimaldi11 (regarded by many as the world’s greatest clown)

has him visiting a doctor without his make up, after which the doctor describes him ‘as the most depressed man I have ever come across’. The doctor then says there is one solution to help raise a smile; he suggests that his ‘patient’ should go that very night to see the great Grimaldi, at which point Grimaldi resignedly reveals who he is to the doctor.

Summary

General Practitioners and psychological specialists should remember to treat and assess both mood and cognition in depression for those at work, whether work be office based, sports or in the arts. Traditional therapies often can help mood but may not improve cognition and, without the right thinking capabilities, it is hard for many to maintain their professional roles. For those with major depression who cannot work because of their poor cognitive function, a medication that can improve this has obvious benefits and fortunately is now recommended by NICE. Self-help tools for patients can also be encouraged and for some it may be useful to know that they can refer themselves faster to a Primary Care Mental Health Team (Improving Access to Psychological Therapies or IAPT12) rather than waiting for you, as their General Practitioner, to refer them to the Community Mental Health Team.

Traditional therapies often can help mood but may not improve cognition and without the right thinking capabilities it is hard for many to maintain their professional roles

References:

1 http://theconversation.com/winston-churchill-and-his-black-dog-of-greatness-36570 Accessed 20/4/2016

2 http://www.legislation.gov.uk/ukpga/2010/15/contents Accessed 20/4/2016

3 https://www.gov.uk/government/collections/fit-note Accessed 20/4/2016

4 http://www.rcpsych.ac.uk/healthadvice/problemsdisorders/depression.aspx Accessed 21/4/2016

5 http://www.theguardian.com/sport/2011/jun/21/marcus-trescothick-interview Accessed 20/4/2016

6 http://www.dailymail.co.uk/sport/cricket/article-3267021/Andrew-Flintoff-Cricket-s-great-showman-fighting-demons-bravado-act-scared-alcohol-escape-checks-depression.html Accessed 20/4/2016

7 http://www.thejustincampaign.com/ Accessed 20/4/2016

8 https://en.wikipedia.org/wiki/Tony_Hancock Accessed 20/4/2016

9 http://www.sane.org.uk/what_we_do/bdt Accessed 20/4/2016

10 https://www.amazon.co.uk/Beyond-Joke-Inside-World-Stand-up-Comedy/dp/0099558270/280-4819008-0962465?ie=UTF8&*Version*=1&*entries*=0 Accessed 20/4/2016

11 http://www.vam.ac.uk/content/articles/g/grimaldi-the-clown/ Accessed 20/4/2016

12 http://www.iapt.nhs.uk/ Accessed 21/4/2016

The Depression1 Challenge for the GP

Dr Charlie Easmon MBBS MRCP MSc Public Health DTM&H DOccMed, Editor

Depression is a common disorder that can have a debilitating effect on a person’s life. It is characterised by persistent sadness, loss of interest or pleasure, feelings of guilt or low self worth, disturbed sleep, appetite and libido, tiredness and poor concentration. It is also often accompanied by feelings of hopelessness and suicidal thoughts, and can lead to suicide. Depression can last from weeks to years, and can be recurrent. It can substantially impair an individual’s ability to function at work or cope with daily life. Treatments for depression include a range of psychological therapies and antidepressant medications. In severe depression that has not responded to other treatments, electroconvulsive therapy is sometimes used.2

MENTAL HEALTH has always been described as a “Cinderella’ service and as such is underfunded and not always fit for purpose. Sadly, despite government efforts, there is no Prince Charming, no ball and no carriage led by pretty white horses, just a poorly dressed service, in ‘pumpkin’ locations. Community mental health teams do the best they can but are under-resourced in time and people.

Treatment or Counselling?

The GP confronted by someone in a depressive mood ideally has time to assess them properly and this may or may not involve the use of questionnaires such as the Patient Health Questionnaire3 (PHQ-9), the Hospital Anxiety and Depression Scale4 (HADS), the Beck Depression Inventory5 (BDI) or the Depression Anxiety Stress Scale6 (DASS) amongst others. Once the diagnosis is made it is important to explain to the patient the chronic nature of the disease before discussing therapy options. For some, limited treatment or no treatment is required. Others will need counselling, medication or both. Those that can get counselling, depending on a post code lottery, may need to wait a long time in the public sector (sometimes as long as 6 months) but if private solutions are affordable, then the British Association for Counselling and Psychotherapy (http://www.bacp.co.uk) is a useful resource. Some charities, such as Fresh Start Psychotherapy7, also offer a much reduced rate on the basis that patients pay what

they can afford and accept that they are seen by the best year 2 students, who are supervised by specialists.

When medication is required it should be explained to the patient that each needs to be tried for effect and if the effect is not successful then either an increase or a switch of medication needs to be tried. Different medications affect different symptoms and it is important to realise that, for cognitive symptoms, a relatively new medication is recognised as the most effective treatment.

Different Forms of Treatment

Other treatment options include the use of electricity or magnetism. Electricity in the form of Electro-Convulsive Therapy (ECT) has developed a bad name and seems to some as barbaric as

VORTIOXETINE MOLECULE

The GP has many treatment options and has to find the right mixture for each patient

they imagine someone strapped to a bed and convulsing wildly as electricity is pumped into their brain. The reality is different and much milder and, in severe cases of depression, can be transformative. Many patients (if not all) will be aware of ‘Star Wars’ and it is perhaps useful to tell them that the actress who plays Princess Leia in the films (Carrie Fisher) is very open about her manic-depressive disorder and its treatments. She writes amusingly on the subject and one of her books is called ’Shockaholic8” and shows how she has benefited from ECT when required. A milder version of ECT is Trans Cranial Direct Current Stimulation9 .

Since the 1960s, research has been conducted on the effects of magnetism on depression and researchers at Harvard and Yale have confirmed that the use of Repetitive Transcranial Magnetic Stimulation (rTMS) can cure 27% of cases of depression. The treatment sessions are short at around 30 minutes, at least 6 are required and there is no anaesthetic, with the patient fully conscious throughout. Very few side effects10 have been noted and The National Institute for Health and Care Excellence (NICE) in December 201511 approved the use of this therapy in depression.

Repetitive transcranial magnetic stimulation (rTMS) does not need anaesthesia and can be done on an outpatient basis. A purpose made electromagnetic coil is held against the scalp with the intention of inducing electric currents in the cerebral cortex. Imaging may be used to help target specific areas of the brain. Treatment is usually considered for patients with depression that has not responded to antidepressant medication or patients for whom antidepressants are not suitable.

References:

In rTMS, repetitive pulses of electromagnetic energy are delivered at various frequencies or stimulus intensities. Conventional rTMS is a repetition of individual pulses at a pre set interval (train of pulses), whereas theta burst rTMS is a repetition of short bursts of pulses at a pre set interval (train of bursts). Stimulation can either be delivered unilaterally, over the left or right dorsolateral prefrontal cortex, or bilaterally over both cortices. Bilateral stimulation may be done sequentially or simultaneously. Treatment with rTMS usually comprises daily sessions lasting about 30 minutes, typically for 2 to 6 weeks.

Summary

The GP has many treatment options and has to find the right mixture for each patient. Fortunately both NICE and the Royal College of Psychiatrists provide excellent advice and guidance.

1 https://www.nice.org.uk/guidance/qs8 Accessed 18/4/2016

2 https://www.nice.org.uk/guidance/ipg542/chapter/2-Indications-and-current-treatments Accessed 18/4/2016

3 http://patient.info/doctor/patient-health-questionnaire-phq-9 Accessed 18/4/2016

4 http://hqlo.biomedcentral.com/articles/10.1186/1477-7525-1-29 Accessed 18/4/2016

5 http://www.apa.org/pi/about/publications/caregivers/practice-settings/assessment/tools/beck-depression.aspx Accessed 18/4/2016

6 http://www2.psy.unsw.edu.au/dass/ Accessed 18/4/2016

7 http://www.freshstartpsychotherapy.co.uk/ Accessed 22/4/2016

8 http://www.freshstartpsychotherapy.co.uk/

9 http://www.amazon.com/Shockaholic-Carrie-Fisher/dp/0743264835/ref=asap_bc?ie=UTF8 Accessed 18/4/2016

10 https://www.nice.org.uk/guidance/ipg530 Accessed 18/4/2016

11 https://www.nice.org.uk/guidance/IPG542/chapter/5-Safety Accessed 18/4/2016

12 https://www.nice.org.uk/guidance/ipg542/ifp/chapter/what-has-nice-said Accessed 18/4/2016

Community mental health teams do the best they can but are under-resourced in time and people

The Polar Aspects of Depression

Jane Carmichael, Medical Correspondent

Depression can be seen as one end of a spectrum of disorders that can include 2 other types of disorder – these are Bipolar 1 and Bipolar 21. Bipolar 1 is more popularly known as manic-depression as suffered by well-known names such as Stephen Fry2, the multi-talented actor, writer and pundit. Bipolar 2 has milder phases of ‘up’ behaviour described as hypomania rather than full mania. Leading actress, Catherine Zeta-Zones3 married to Michael Douglas, revealed herself to have Bipolar 2 after he had been diagnosed with throat cancer.

Bipolar 1 and Bipolar 2

The manic-depressive may have ‘normal’ periods, depressive periods and manic ones. During the manic phases they lose control of rational thought and behave in a manner that can be seen as ’wild’ and ‘out of control’. This phase may lead to excessive spending, the use of drugs and alcohol to excess and uninhibited sexual activity. Ironically, even whilst behaving in this way, it is known that some manic-depressives have ‘insight’ and feel sad about their own behaviour whilst they are behaving oddly. Some people, as in poker, have a ‘tell’ i.e. a clue as to when their mania is increasing. One excellent doctor would start to wear more red and by the time she was completely in red, those who knew her also knew this was the time for her to rest or increase her medication. Historically, Lithium has been one of the most common treatments for this condition but Lithium like warfarin has a narrow therapeutic/ toxic range and needs to be properly monitored.

For the formal diagnosis of a Bipolar 1 disorder, the abnormally elevated mood or irritability and related symptoms with ‘severe functional impairment or psychotic symptoms4’ would be expected to last at least 7 days or more, with lesser symptoms for a shorter duration of 4 days or more in the hypomania of Bipolar 2.

Both Bipolar 1 and 2 are often co-morbid with other disorders, which may include substance misuse, personality disorders, anxiety disorders and attention deficit (hyperactivity) disorder ADHD.

It is important to distinguish the bipolar

conditions from other conditions such as Borderline Personality Disorder5 (BPD). BPD can have similar mood swings but the important feature is time and the speed of the changes, which can be within 24 hours in BPD but are in weeks or months in true Bipolar conditions. So, if we think of the phases as waves with similar amplitudes up and down, the frequency of the waves is much faster in BPD and much slower in true bipolar conditions.

Treating Bi-Polar Depression

The National Institute for Health and Care Excellence (NICE) emphasises person-centered care6 and the challenge for health professionals is to do more listening than talking. Patients have rights but it is important to try to protect them for harming themselves physically, psychologically, socially, reputationally and in other ways. During a period of mania or hypomania specific medication is likely to be needed or adjusted. Some will need or be on Lithium. The dose of Lithium may need to be increased or another medication added. Others may be better off on medication other than Lithium7

Appropriate talking therapy from someone trained in managing bipolar issues may be helpful and this may range from interpersonal, cognitive behavioural to behavioral couples therapy.

A key aspect of care for those with bipolar disorders is care for their carers8, who unsurprisingly, may become worn out and exhausted9

Treatment for the co-morbid conditions associated with Bipolar 1 and 2 must always be considered and supported. For those with substance misuse the challenge may be to intervene at the point at which the person has enough ‘insight’ to know they need to change. Sadly in some cases, this only occurs when they have hit some form of rock bottom. If rehabilitation is required, this needs a safe place of rest with therapy, appropriate counselling and de-toxification. The de-toxification may require benzodiazepines to deal with the withdrawal symptoms and anxiety. Not everyone believes in the 12 steps principles of Alcoholics Anonymous10 but it cannot be denied that it has helped millions

The challenge for health professionals is to do more listening than talking

of addicts worldwide, as have the associated groups of Narcotics Anonymous11 and Sexaholics Anonymous12. The addict is faced by temptation every day and everywhere they go. Try travelling on a plane and not being offered an alcoholic dink. In many US hotels the receptionist will keep a list of local Alcoholics Anonymous centres and this practical idea might be good to introduce in the UK.

Identifying Types of Personality Disorders

Those with personality disorders need the ones that affect them identified. The World Health Organization’s International Classification of Diseases (ICD- 10)13 recognises 10 whereas DSM-514 has some differences in recognition and definition. Three broad categories of Personality Disorder are recognised – these are Cluster A: ‘Odd or Eccentric; Cluster B: ‘Dramatic, Emotional, or Erratic’; Cluster C: ‘Anxious and Fearful’15. Within Cluster A are included Paranoid (these people are suspicious, they feel that other people are being nasty to them (despite evidence showing that this isn’t true). They feel easily rejected and often tend to hold grudges); Schizoid (this group are emotionally ‘cold’, they don’t like contact with other people, prefer their own company and often have a rich fantasy world); Schizotypal (this group demonstrate eccentric behaviour, have odd ideas, difficulties with thinking, may show lack of emotion, or inappropriate emotional reactions, see or hear strange things and this is sometimes related to schizophrenia, the mental illness).

Within Cluster B are Antisocial, or Dissocial – this group don’t care much about the feelings of others, get easily get frustrated, tend to be aggressive, commit crimes, find it difficult to make close relationships, are often impulsive – do things

on the spur of the moment without thinking about them, they don’t feel guilty about things they’ve done and, sadly, they don’t learn from unpleasant experiences; Borderline, or Emotionally Unstable – this group are impulsive – do things on the spur of the moment, they find it hard to control their emotions, feel bad about themselves, often self-harm, feel ‘empty’, make relationships quickly, but easily lose them, partners go from ‘hero’ to ‘zero’ rapidly, they can feel paranoid or depressed and when stressed they may hear noises or voices; Histrionic – this group overdramatise events, they are self-centered, have strong emotions which change quickly and don’t last long, they can be suggestible, worry a lot about their appearance, crave new things and excitement and can be seductive; Narcissistic – this group have a strong sense of their own self-importance, dream of unlimited success, power and intellectual brilliance, crave attention from other people, but show few warm feelings in return and they often take advantage of other people and/or ask for favours that they do not then return.

Within Cluster C are Obsessive-Compulsive (aka Anankastic) – this group worry and doubt a lot, they are perfectionist, rigid in what they do, stick to routines, are cautious, preoccupied with detail, worry about doing the wrong thing, find it hard to adapt to new situations, often have high moral standards, are judgmental, sensitive to criticism and can have obsessional thoughts and images (although these are not as bad as those in obsessive-compulsive disorder); Avoidant (aka Anxious/Avoidant) – this group are very anxious and tense, worry a lot, they feel insecure and inferior, have to be liked and accepted and are extremely sensitive to criticism; Dependent – this group are passive, they rely on others to make decisions for them, do what other people

The differentiation of Bipolar disorders from purely reactive or endogenous depression and the assessment of possible co-morbidities is essential to ensure the right medication and therapy

want them to do, find it hard to cope with daily chores, feel hopeless and incompetent and easily feel abandoned by others

Personality disorders are estimated to affect 5-20% of the population and anyone person can have more than one and/or some degree of overlap. Specific therapy is required to help each. Anxiety disorders are common and, in fact, social anxiety disorder can be seen as a type of Personality Disorder.

Attention Deficit (Hyperactivity) Disorder

ADHD16 may be without the (H) for hyperactivity. If hyperactivity is included then fidgeting, excess movement, interrupting conversations and excessive talking may feature . If it is not included, the individual is likely to have problems organising,

prioritising and concentrating without getting distracted.

Summary

When the General Practitioner sees someone in a depressive phase for the first time they should always consider whether this is just one part of a cycle and, if that cycle lasts days, it is more likely to be Bipolar 1 or 2 than Borderline Personality Disorder (which has mood changes within hours rather than days!).

The differentiation of Bipolar disorders from purely reactive or endogenous depression and the assessment of possible co-morbidities is essential to ensure the right medication and therapy.

References:

1 http://www.webmd.com/bipolar-disorder/guide/bipolar-2-disorder Accessed 18/4/2016

2 http://www.bbc.co.uk/programmes/b07187tc Accessed 22/4/2016

3 http://www.telegraph.co.uk/news/picturegalleries/celebritynews/9677936/Catherine-Zeta-Jones-speaks-out-about-her-battle-with-manic-depression.html Accessed 18/4/2016

4 https://www.nice.org.uk/guidance/cg185/chapter/Introduction Accessed 21/4/2016

5 http://www.nhs.uk/conditions/borderline-personality-disorder/Pages/Introduction.aspx Accessed 21/4/2016

6 https://www.nice.org.uk/guidance/cg185/chapter/Personcentred-care Accessed 21/4/2016

7 https://www.nice.org.uk/guidance/cg185/chapter/Key-priorities-for-implementation#recognising-and-managing-bipolar-disorder-in-adults-in-primary-care Accessed 21/4/2016

8 http://www.carersuk.org/news-and-campaigns/press-releases/carers-pushed-to-breaking-point Accessed 22/4/2016

9 http://pathways.nice.org.uk/pathways/bipolar-disorder#content=view-node%3Anodes-support-for-carers Accessed 21/4/2016

10 http://www.alcoholics-anonymous.org.uk/ Accessed 22/4/2016

11 http://ukna.org/ Accessed 22/4/2016

12 http://www.sa.org/ Accessed 22/4/2016

13 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1525106/ Accessed 22/4/2016

14 https://en.wikipedia.org/wiki/Diagnostic_and_Statistical_Manual_of_Mental_Disorders#DSM-5_.282013.29 Accessed 22/4/2016

15 http://www.rcpsych.ac.uk/mentalhealthinfo/problems/personalitydisorders/personalitydisorder.aspx Accessed 22/4/2016

16 http://www.nhs.uk/conditions/attention-deficit-hyperactivity-disorder/Pages/Introduction.aspx Accessed 22/4/2016

17 http://www.nhs.uk/Conditions/Attention-deficit-hyperactivity-disorder/Pages/Symptoms.aspx Accessed 22/4/2016

Personality disorders are estimated to affect 5-20% of the population and anyone person can have more than one and/or some degree of overlap. Specific therapy is required to help each

Notes:

Notes:

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