Psychotropic drugs in overdose

Suicide attempts and suicidal gestures are frequently encountered in psychiatric and general practice, and psychotropic drugs are often taken in overdose. This section gives brief details of the toxicity in overdose of commonly used psychotropics (Table 8.1). It is intended to help guide drug choice in those thought to be at risk of suicide and to help identify symptoms of overdose. This section gives no information on the treatment of psychotropic overdose and readers are directed to specialist poisons units. In all cases of suspected overdose, urgent referral to acute medical facilities is, of course, strongly advised.

Table 8.1 Psychotropic drugs in overdose

References

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26. Jimmink A et al. Clinical toxicology of citalopram after acute intoxication with the sole drug or in combination with other drugs: overview of 26 cases. Ther Drug Monit 2008; 30:365–371.
27. Tarabar AF et al. Citalopram overdose: late presentation of torsades de pointes (TdP) with cardiac arrest. J Med Toxicol 2008; 4:101–105.
28. Yilmaz Z et al. Escitalopram causes fewer seizures in human overdose than citalopram. Clin Toxicol (Phila) 2010; 48:207–212.
29. van GF et al. Clinical and ECG effects of escitalopram overdose. Ann Emerg Med 2009; 54:404–408.
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31. Martinez MA et al. Investigation of a fatality due to trazodone poisoning: case report and literature review. J Anal Toxicol 2005; 29:262–268.
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36. Huang SS et al. Low-dose venlafaxine-induced severe rhabdomyolysis: a case report. Gen Hosp Psychiatry 2012; 34:436–437.
37. Batista M et al. The spectrum of acute heart failure after venlafaxine overdose. Clin Toxicol (Phila) 2013; 51:92–95.
38. Whyte IM et al. Relative toxicity of venlafaxine and selective serotonin reuptake inhibitors in overdose compared to tricyclic antidepressants. QJM 2003; 96:369–374.
39. Howell C et al. Cardiovascular toxicity due to venlafaxine poisoning in adults: a review of 235 consecutive cases. Br J Clin Pharmacol 2007; 64:192–197.
40. Hojer J et al. Fatal cardiotoxicity induced by venlafaxine overdosage. Clin Toxicol (Phila) 2008; 46:336–337.
41. Taylor D. Venlafaxine and cardiovascular toxicity. BMJ 2010; 340:327.
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44. Ward DI. Two cases of amisulpride overdose: A cause for prolonged QT syndrome. Emerg Med Australas 2005; 17:274–276.
45. Isbister GK et al. Amisulpride overdose is frequently associated with QT prolongation and torsades de pointes. J Clin Psychopharmacol 2010; 30:391–395.
46. Lofton AL et al. Atypical experience: a case series of pediatric aripiprazole exposures. Clin Toxicol (Phila) 2005; 43:151–153.
47. Seifert SA et al. Aripiprazole (abilify) overdose in a child. Clin Toxicol (Phila) 2005; 43:193–195.
48. Carstairs SD et al. Overdose of aripiprazole, a new type of antipsychotic. J Emerg Med 2005; 28:311–313.
49. Forrester MB. Aripiprazole exposures reported to Texas poison control centers during 2002-2004. J Toxicol Environ Health A 2006; 69:1719–1726.
50. Taylor JE et al. A case of intentional asenapine overdose. Prim Care Companion CNS Disord 2013; 15.
51. Haddad PM et al. Antipsychotic-related QTc prolongation, torsade de pointes and sudden death. Drugs 2002; 62:1649–1671.
52. Levine BS et al. Two fatalities involving haloperidol. J Anal Toxicol 1991; 15:282–284.
53. Henderson RA et al. Life-threatening ventricular arrhythmia (torsades de pointes) after haloperidol overdose. Hum Exp Toxicol 1991; 10:59–62.
54. Trenton A et al. Fatalities associated with therapeutic use and overdose of atypical antipsychotics. CNS Drugs 2003; 17:307–324.
55. Flanagan RJ et al. Suspected clozapine poisoning in the UK/Eire, 1992-2003. Forensic Sci Int 2005; 155:91–99.
56. Vigneault P et al. Iloperidone (Fanapt(R)), a novel atypical antipsychotic, is a potent HERG blocker and delays cardiac ventricular repolarization at clinically relevant concentration. Pharmacol Res 2012; 66:60–65.
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58. Sunovion Pharmaceuticals Inc. Highlights of Prescribing Information: LATUDA (lurasidone hydrochloride) tablets. 2013. http://www.latuda. com/LatudaPrescribingInformation.pdf
59. Chue P et al. A review of olanzapine-associated toxicity and fatality in overdose. J Psychiatry Neurosci 2003; 28:253–261.
60. Waring WS et al. Olanzapine overdose is associated with acute muscle toxicity. Hum Exp Toxicol 2006; 25:735–740.
61. Morissette P et al. Olanzapine prolongs cardiac repolarization by blocking the rapid component of the delayed rectifier potassium current. J Psychopharmacol 2007; 21:735–741.
62. Buckley NA et al. Cardiotoxicity more common in thioridazine overdose than with other neuroleptics. J Toxicol Clin Toxicol 1995; 33:199–204.
63. Li C et al. Acute pulmonary edema induced by overdosage of phenothiazines. Chest 1992; 101:102–104.
64. Flanagan RJ. Fatal toxicity of drugs used in psychiatry. Hum Psychopharmacol 2008; 23 Suppl 1:43–51.
65. Langman LJ et al. Fatal overdoses associated with quetiapine. J Anal Toxicol 2004; 28:520–525.
66. Hunfeld NG et al. Quetiapine in overdosage: a clinical and pharmacokinetic analysis of 14 cases. Ther Drug Monit 2006; 28:185–189.
67. Strachan PM et al. Mental status change, myoclonus, electrocardiographic changes, and acute respiratory distress syndrome induced by quetiapine overdose. Pharmacotherapy 2006; 26:578–582.
68. Ngo A et al. Acute quetiapine overdose in adults: a 5-Year retrospective case series. Ann Emerg Med 2008; 52: 541–547.
69. Khan KH et al. Neuroleptic malignant syndrome induced by quetiapine overdose. Br J Hosp Med 2008; 69:171.
70. Alexander J. Delirium as a symptom of quetiapine poisoning. Aust N Z J Psychiatry 2009; 43:781.
71. Liang CS et al. Acute renal failure after paliperidone overdose: a case report. J Clin Psychopharmacol 2012; 32:128.
72. Lapid MI et al. Acute dystonia associated with paliperidone overdose. Psychosomatics 2011; 52:291–294.
73. Gomez-Criado MS et al. Ziprasidone overdose: cases recorded in the database of Pfizer-Spain and literature review. Pharmacotherapy 2005; 25:1660–1665.
74. Arbuck DM. 12,800-mg ziprasidone overdose without significant ECG changes. Gen Hosp Psychiatry 2005; 27:222–223.
75. Insa Gomez FJ et al. Ziprasidone overdose: cardiac safety. Actas Esp Psiquiatr 2005; 33:398–400.
76. Klein-Schwartz W et al. Prospective observational multi-poison center study of ziprasidone exposures. Clin Toxicol (Phila) 2007; 45:782–786.
77. Tan HH et al. A systematic review of cardiovascular effects after atypical antipsychotic medication overdose. Am J Emerg Med 2009; 27:607–616.
78. Alipour A et al. Torsade de pointes after ziprasidone overdose with coingestants. J Clin Psychopharmacol 2010; 30:76–77.
79. Spiller HA. Management of carbamazepine overdose. Pediatr Emerg Care 2001; 17:452–456.
80. Schmidt S et al. Signs and symptoms of carbamazepine overdose. J Neurol 1995; 242:169–173.
81. Miller MA et al. Choreiform dyskinesia following isolated lamotrigine overdose. J Child Neurol 2008; 23:243.
82. Reimers A et al. Acute lamotrigine overdose in an adolescent. Ther Drug Monit 2007; 29:669–670.
83. Lofton AL et al. Evaluation of lamotrigine toxicity reported to poison centers. Ann Pharmacother 2004; 38:1811–1815.
84. Tuohy K et al. Acute lithium intoxication. Dial Transplant 2003; 32:478–481.
85. Chen KP et al. Implication of serum concentration monitoring in patients with lithium intoxication. Psychiatry Clin Neurosci 2004; 58:25–29.
86. Serinken M et al. Rarely seen cardiotoxicity of lithium overdose: complete heart block. Int J Cardiol 2009; 132:276–278.
87. Offerman SR et al. Hospitalized lithium overdose cases reported to the California Poison Control System. Clin Toxicol (Phila) 2010; 48:443–448.
88. Isbister GK et al. Valproate overdose: a comparative cohort study of self poisonings. Br J Clin Pharmacol 2003; 55:398–404.
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90. Sztajnkrycer MD. Valproic acid toxicity: overview and management. J Toxicol Clin Toxicol 2002; 40:789–801.
91. Eyer F et al. Acute valproate poisoning: pharmacokinetics, alteration in fatty acid metabolism, and changes during therapy. J Clin Psychopharmacol 2005; 25:376–380.
92. Robinson P et al. Severe hypothermia in association with sodium valproate overdose. N Z Med J 2005; 118:U1681.
93. Reith DM et al. Comparison of the fatal toxicity index of zopiclone with benzodiazepines. J Toxicol Clin Toxicol 2003; 41:975–980.
94. Isbister GK et al. Alprazolam is relatively more toxic than other benzodiazepines in overdose. Br J Clin Pharmacol 2004; 58:88–95.
95. Gable RS. Comparison of acute lethal toxicity of commonly abused psychoactive substances. Addiction 2004; 99:686–696.
96. Caplehorn JR et al. Fatal methadone toxicity: signs and circumstances, and the role of benzodiazepines. Aust N Z J Public Health 2002; 26:358–362.
97. Spiller HA et al. Toxicity from modafinil ingestion. Clin Toxicol (Phila) 2008;1-4.
98. Carstairs SD et al. A retrospective review of supratherapeutic modafinil exposures. J Med Toxicol 2010; 6:307–310.
99. Gock SB et al. Acute zolpidem overdose: report of two cases. J Anal Toxicol 1999; 23:559–562.
100. Garnier R et al. Acute zolpidem poisoning: analysis of 344 cases. J Toxicol Clin Toxicol 1994; 32:391–404.
101. Pounder D et al. Zopiclone poisoning. J Anal Toxicol 1996; 20:273–274.
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Biochemical and haematological effects of psychotropics

Almost all psychotropics currently used in clinical practice have haematology or biochemistry-related adverse effects that may be detected using routine blood tests. While many of these changes are idiosyncratic and not clinically significant, others, such as the agranulocytosis associated with agents such as clozapine, will require regular monitoring of the full blood count. In general, where an agent has a high incidence of biochemical/haematological side-effects or a rare but potentially fatal effect, regular monitoring is required as discussed in other sections.

For other agents, laboratory-related side-effects are comparatively rare (prevalence usually less than 1%), are often reversible upon cessation of the putative offending agent and not always clinically significant although expert advice should be sought. It should further be noted that medical co-morbidity, polypharmacy and the effects of non-prescribed agents, including substances of abuse and alcohol, may also influence biochemical and haematological parameters. In some cases, where a clear temporal association between starting the agent and the onset of laboratory changes is unclear, then withdrawal and re-challenge with the agent in question may be considered. Where there is doubt as to the aetiology and significance of the effect, the appropriate source of expert advice should always be consulted.

Tables 8.2 and 8.3 summarise those agents with identified biochemical and haematological effects, with information compiled from various sources.^1–11 In many cases the evidence for these various effects is limited, with information obtained mostly from case reports, case series and information supplied by manufacturers. For further details about each individual agent, the reader is encouraged to consult the appropriate section of the Guidelines as well as other, specialist sources, particularly product literature relating to individual drugs.

Table 8.2 Summary of biochemical changes associated with psychotropic drugs

Table 8.3 Summary of haematological changes associated with psychotropic drugs

References

1. Balon R et al. Hematologic side effects of psychotropic drugs. Psychosomatics 1986; 27:119–127.
2. Bazire S. Psychotropic Drug Directory. UK: Lloyd-Reinhold Communcations LLP; 2014.
3. Joint Formulary Committee. BNF 67 March-September 2014 (online). London: Pharmaceutical Press; 2014. http://www.medicinescomplete. com/mc/bnf/current/
4. Aronson JK. Meyler's Side Effects of Drugs: The International Encyclopedia of Adverse Drug Reactions and Interactions, 15th edn. Amsterdam: Elsevier Science; 2006.
5. Foster R. Clinical Laboratory Investigation and Psychiatry. A Practical Handbook. New York: Informa; 2008.
6. Jacobs DS et al. Laboratory Test Handbook, 5th edn. Hudson, Cleveland: Lexi-Comp Inc; 2001.
7. Livingstone C et al. The role of clinical biochemistry in psychiatry. Clin Biochem 2004; 6:59–65.
8. Oyesanmi O et al. Hematologic side effects of psychotropics. Psychosomatics 1999; 40:414–421.
9. Stubner S et al. Blood dyscrasias induced by psychotropic drugs. Pharmacopsychiatry 2004; 37 Suppl 1:S70–S78.
10. Martindale: The Complete Drug Reference. London: Pharmaceutical Press; 2014. http://www.medicinescomplete.com
11. Wu AHB. Tietz Clinical Guide to Laboratory Tests, 4th edn. Philadelphia, Pennsylvania: WB Saunders and Company; 2006.

Prescribing drugs outside their licensed indications
('off-label' prescribing)

A Product Licence (PL) is granted when regulatory authorities are satisfied that the drug in question has proven efficacy in the treatment of a specified disorder, along with an acceptable side-effect profile, relative to the severity of the disorder being treated and other available treatments. Licensed indications are preparation specific, outlined in the Summary of Product Characteristics (SPC), and may be different for branded and generic formulations of the same drug.¹ In the US product 'labelling' has a similar legal status to EU licensing.

The decision of a manufacturer to seek a PL for a given indication is essentially a commercial one; potential sales are balanced against the cost of conducting the necessary clinical trials. It therefore follows that drugs may be effective outside their licensed indications for different disease states, age ranges, doses and durations. The absence of a formal PL or labelling may simply reflect the absence of controlled trials supporting the drug's efficacy in these areas. In other cases (e.g. sertraline or quetiapine in generalised anxiety disorder) there is sufficient evidence but a licence has not been sought by the manufacturer. Importantly, however, it is possible that trials have been conducted but given negative results. Clinicians often assume that drugs with a similar mode of action will be similarly effective for a given indication, and in many cases this may be true. For example, the efficacy of aripiprazole, olanzapine, quetiapine and risperidone in reducing behavioural and psychological symptoms (BPSD) in people with dementia, is similar² yet only risperidone is licensed for this indication.

Prescribing a drug within its licence or labelling does not guarantee that the patient will come to no harm. Likewise, prescribing outside a licence does not mean that the risk–benefit ratio is automatically adverse. In the BPSD example given above, risperidone is not clearly better tolerated than other antipsychotics.² In the UK, prescribing outside a licence, usually called 'off-label', does confer extra responsibilities on prescribers, who will be expected to be able to show that they acted in accordance with a respected body of medical opinion (the Bolam test)³ and that their action was capable of withstanding logical analysis (the Bolitho test).⁴

It has been suggested that off-label prescribing in psychiatry is less likely to be supported by a strong evidence base than off-label prescribing in other areas of medicine.⁵ In psychiatry, small (underpowered) studies (with wide confidence intervals) often influence practice, particularly with respect to treatment resistant illness. When these small studies are combined in the form of a meta-analysis, considerable heterogeneity is often found suggesting publication bias (that is, that negative studies are not published). Treatments may therefore become incorporated into 'routine custom and practice' in the absence of any evidence supporting efficacy and/or tolerability, and these treatments may sometimes continue to be used despite the findings of later, larger, and more definitive negative studies.

The psychopharmacology special interest group at the Royal College of Psychiatrists has published a consensus statement on the use of licensed medicines for unlicensed uses.⁶ They note that unlicensed use is common in general adult psychiatry with cross-sectional studies showing that up to 50% of patients are prescribed at least one drug outside the terms of its licence. They also note that the prevalence of this type of prescribing is likely to be higher in patients under the age of 18 or over 65, in those with a learning disability, in women who are pregnant or lactating and in those patients who are cared for in forensic psychiatry settings. The main recommendations in the consensus statement are summarised in Box 8.1.

Examples of acceptable use of drugs outside their Product Licences/Labels

Table 8.4 gives examples of common unlicensed uses of drugs in psychiatric practice. These examples would all fulfil the Bolam and Bolitho criteria in principle. An exhaustive list of unlicensed uses is impossible to prepare as:

• the evidence base is constantly changing
• the expertise and experience of prescribers varies. A strategy may be justified in the hands of a specialist in psychopharmacology based in a tertiary referral centre but be much more difficult to justify if initiated by someone with a special interest in psychotherapy who rarely prescribes.

Note that some drugs do not have a UK licence for any indication. Two commonly prescribed examples in psychiatric practice are immediate release formulations of melatonin (used to treat insomnia in children and adolescents) and pirenzepine (used to treat clozapine-induced hypersalivation). Awareness of the evidence base and documentation of potential benefits, side-effects and patient consent are especially important here.

Table 8.4 Common unlicensed uses of drugs in psychiatric practice

References

1. Datapharm Communications Ltd. Summary of Product Characteristics. Electronic Medicines Compendium. 2014. http://www.medicines.org. uk/emc/
2. Maher AR et al. Efficacy and comparative effectiveness of atypical antipsychotic medications for off-label uses in adults: a systematic review and meta-analysis. JAMA 2011; 306:1359–1369.
3. Bolam v Friern Barnet Hospital Management Committee. WLR 1957; 1:582.
4. Bolitho v City and Hackney Health Authority. WLR 1997; 3:1151.
5. Epstein RS et al. The many sides of off-label prescribing. Clin Pharmacol Ther 2012; 91:755–758.
6. Royal College of Psychiatrists. College Report 142. Use of licensed medicines for unlicensed applications in psychiatric practice. 2007. http://www.rcpsych.ac.uk/publications/collegereports/cr/cr142.aspx

Further reading

Frank B et al. Psychotropic medications and informed consent: a review. Ann Clin Psychiatry 2008; 20:87–95.

General Medical Council. Good practice in prescribing and managing medicines and devices. 2013. http://www.gmc-uk.org/guidance/ethical_guidance/14316.asp.

Observations on the placebo effect in mental illness

Target symptoms improve to varying degrees in approximately one-third of patients given a placebo.^1,2 Adverse effects also occur; the so-called nocebo effect.² Although pharmacologically inert, placebo can cause direct physiological effects, at least in the short term, that are consistent with the effects of active drugs. This has been demonstrated in neuroimaging studies.^3,4 The exact neurobiological response varies with the target illness.^2,5 In many psychiatric conditions the effect size of placebo is substantial;⁶ often greater than the effect size of drugs used in general medicine.⁷ Proving the efficacy of psychotropic drugs is thus challenging; much more challenging than in general medicine where placebo effects are often absent (e.g. type I diabetes).

The following considerations apply when interpreting the results of placebo-controlled studies. Although the references for each point are drawn from the depression literature, the same principles apply to the treatment of other disorders. The relative importance of each point will vary depending on the disorder that is being treated.

• Placebo is not the same as no care: patients who maintain contact with services have a better outcome than those who receive no care.⁸
• The placebo response is greater in mild illness.^9,10
• Placebo tablets and controls for the non-specific effects of psychological interventions such as CBT may not be equitable,¹¹ leading to an overestimation of the benefits of psychological relative to pharmacological interventions.
• The higher the placebo response rate, the more difficult it is to power studies to show treatment effects. Where the placebo response rate exceeds 40%, studies have to recruit very large numbers of patients to be adequately powered to show differences between treatments.¹² For example, it has been demonstrated in a novel analysis that 39% of participants in placebo-controlled RCTs of escitalopram respond irrespective of treatment allocation, with just 19% of the total benefit attributable to active treatment.¹⁰ The large placebo response rate results in a small overall absolute difference between the active and placebo arms but within this small 'effect size' a proportion of patients improve markedly with active treatment.
• It is difficult to separate placebo effects from spontaneous remission. The higher the spontaneous remission rate, the more difficult it is to power studies to show treatment effects.⁸
• Patients who enter RCTs generally do so when acutely unwell. Symptoms are likely to improve in the majority, irrespective of the intervention. This is so-called 'regression to the mean'.^11,13
• The placebo response rate in published studies is increasing over time.¹⁴ This may be because of increasing numbers of mildly ill patients being recruited into trials perhaps because of clinicians' reluctance to risk severely ill patients being randomised into placebo arms.
• 'Breaking the blind' may influence outcome. The resultant 'expectancy effect' may explain why active placebos are more effective than inert placebos.^15,16 That is, if patients or observers note adverse effects, the placebo effect is enhanced.
• Overt administration of placebo is more effective than covert administration.²
• Not all placebos are the same. Patients perceive two brightly coloured tablets to be more effective than one small white one. Capsules, injections and branding also increase expectations of efficacy.¹ This may partly explain different placebo response rates in studies of similar design.
• Placebo effects may be cumulative, with two different placebo interventions used simultaneously giving a greater effect than one.²
• Most psychotropic drugs have side-effects such as sedation that may improve scores on rating scales without actually treating the target illness.
• Placebo response may be short-lived: studies are usually too short to pick up placebo relapsers.¹⁷
• Statistical significance and clinical significance are not the same thing: a study may report on a highly statistically significant difference in efficacy between active drug and placebo, but the magnitude of the difference may be too small to be clinically meaningful.
• Publication bias remains a problem.^18–20 Many negative studies are never published.^21,22 Underpowered positive studies often are. Reboxetine is a good example here—considering unpublished studies reveal the drug to have limited, if any, efficacy.²²
• Placebo response increases according to expectancy. For example, placebo response is greater in studies randomising 2:1 active: placebo than in those randomising 1:1 (chance of receiving active is greater).²²
• Placebo and nocebo mechanisms can be additive to those of drug treatment as treatment is given in a therapeutic context that has the potential to activate and modulate placebo mechanisms.^2,23
• Note that other effects may operate: 'wish bias' probably exaggerates the efficacy of new drugs compared with established agents.²⁴
• Placebo shows a dose-related effect. The more visits (assessments) in a trial, the better the effect of placebo.²⁵

References

1. Rajagopal S. The placebo effect. Psychiatr Bull 2006; 30:185–188.
2. Finniss DG et al. Biological, clinical, and ethical advances of placebo effects. Lancet 2010; 375:686–695.
3. Scott DJ et al. Placebo and nocebo effects are defined by opposite opioid and dopaminergic responses. Arch Gen Psychiatry 2008; 65:220–231.
4. Lidstone SC et al. Effects of expectation on placebo-induced dopamine release in Parkinson disease. Arch Gen Psychiatry 2010; 67:857–865.
5. Brody H et al. Lessons from recent research about the placebo effect: from art to science. JAMA 2011; 306:2612–2613.
6. Kirsch I et al. Initial severity and antidepressant benefits: a meta-analysis of data submitted to the Food and Drug Administration. PLoS Med 2008; 5:e45.
7. Leucht S et al. Putting the efficacy of psychiatric and general medicine medication into perspective: review of meta-analyses. Br J Psychiatry 2012; 200:97–106.
8. Andrews G. Placebo response in depression: bane of research, boon to therapy. Br J Psychiatry 2001; 178:192–194.
9. Khan A et al. Severity of depression and response to antidepressants and placebo: an analysis of the Food and Drug Administration database. J Clin Psychopharmacol 2002; 22:40–45.
10. Thase ME et al. Assessing the 'true' effect of active antidepressant therapy v. placebo in major depressive disorder: use of a mixture model. Br J Psychiatry 2011; 199:501–507.
11. Jauhar S et al. Cognitive-behavioural therapy for the symptoms of schizophrenia: systematic review and meta-analysis with examination of potential bias. Br J Psychiatry 2014; 204:20–29.
12. Thase ME. Studying new antidepressants: if there were a light at the end of the tunnel, could we see it? J Clin Psychiatry 2002; 63 Suppl 2:24–28.
13. McDonald CJ et al. How much of the placebo 'effect' is really statistical regression? Stat Med 1983; 2:417–427.
14. Walsh BT et al. Placebo response in studies of major depression: variable, substantial, and growing. JAMA 2002; 287:1840–1847.
15. Kirsch I et al. The Emperor's new drugs: An analysis of antidepressant medication data submitted to the US Food and Drug Administration. Prevention Treatment 2002; 5:10–23.
16. Moncrieff J et al. Active placebos versus antidepressants for depression. Cochrane Database Syst Rev 2004; CD003012.
17. Ross DC et al. A typological model for estimation of drug and placebo effects in depression. J Clin Psychopharmacol 2002; 22:414–418.
18. Lexchin J et al. Pharmaceutical industry sponsorship and research outcome and quality: systematic review. BMJ 2003; 326:1167–1170.
19. Melander H et al. Evidence b(i)ased medicine–selective reporting from studies sponsored by pharmaceutical industry: review of studies in new drug applications. BMJ 2003; 326:1171–1173.
20. Werneke U et al. How effective is St John's wort? The evidence revisited. J Clin Psychiatry 2004; 65:611–617.
21. Turner EH et al. Selective publication of antidepressant trials and its influence on apparent efficacy. N Engl J Med 2008; 358:252–260.
22. Eyding D et al. Reboxetine for acute treatment of major depression: systematic review and meta-analysis of published and unpublished placebo and selective serotonin reuptake inhibitor controlled trials. BMJ 2010; 341:c4737.
23. Grelotti DJ et al. Placebo by proxy. BMJ 2011; 343:d4345.
24. Barbui C et al. "Wish bias" in antidepressant drug trials? J Clin Psychopharmacol 2004; 24:126–130.
25. Posternak MA et al. Therapeutic effect of follow-up assessments on antidepressant and placebo response rates in antidepressant efficacy trials: meta-analysis. Br J Psychiatry 2007; 190:287–292.

Drug interactions with alcohol

Drug interactions with alcohol are complex. Many patient-related and drug-related factors need to be considered. It can be difficult to predict accurately outcomes because a number of processes may occur simultaneously or consequently.

Pharmacokinetic interactions^1–4

Alcohol (ethanol) is absorbed from the gastrointestinal tract and distributed in body water. The volume of distribution is smaller in women and the elderly where plasma levels of alcohol will be higher for a given 'dose' of alcohol than in males. Approximately 10% of ingested alcohol is subjected to first pass metabolism by alcohol dehydrogenase (ADH). A small proportion of alcohol is metabolised by ADH in the stomach. The remainder is metabolised in the liver by ADH and CYP2E1; women have less capacity to metabolise via ADH than men. CYP2E1 plays a minor role in occasional drinkers but is an important and inducible metabolic route in chronic, heavy drinkers. CYP1A2, CYP3A4 and many other CYP enzymes also play a minor role.^5,6

CYP2E1 and ADH convert alcohol to acetaldehyde which is both the toxic substance responsible for the unpleasant symptoms of the 'antabuse reaction' (e.g. flushing, headache, nausea, malaise), and the compound implicated in hepatic damage. Acetaldehyde is further metabolised by aldehyde dehydrogenase to acetic acid and then to carbon dioxide and water.

All of the enzymes involved in the metabolism of alcohol exhibit genetic polymorphism. For example, 40% of people of Asian origin are poor metabolisers via ADH. Chronic consumption of alcohol induces CYP2E1 and CYP3A4. The effects of alcohol on other hepatic metabolising enzymes have been poorly studied.

The metabolism of alcohol is summarised in Figure 8.1.

Interactions are difficult to predict in alcohol misusers because two opposing processes may be at work: competition for enzymatic sites during periods of intoxication (increasing drug plasma levels) and enzyme induction prevailing during periods of sobriety (reducing plasma levels). See Tables 8.5 and 8.6. In chronic drinkers, particularly those who binge drink, serum levels of prescribed drugs may reach toxic levels during periods of intoxication with alcohol and then be sub-therapeutic when the patient is sober. This makes it very difficult to optimise treatment of physical or mental illness.

Figure 8.1 Metabolism of alcohol. *Minor route in occasional drinkers; major route in misusers and at higher blood alcohol concentration.

Interactions of uncertain aetiology include increased blood alcohol concentrations in people who take verapamil and decreased metabolism of methylphenidate in people who consume alcohol.

Table 8.5 Co-administration of alcohol and substrates for CYP2E1 and CYP3A4

Table 8.6 Drugs that inhibit alcohol dehydrogenase and aldehyde dehydrogenase

Pharmacodynamic interactions^2–4,7

Alcohol enhances inhibitory neurotransmission at gamma-aminobutyric acid (GABA) receptors and reduces excitatory neurotransmission at glutamate N-methyl-D-aspartate (NMDA) receptors. It also increases dopamine release in the mesolimbic pathway and may have some effects on serotonin and opiate pathways. Given these actions, alcohol alone would therefore be expected to cause sedation, amnesia, ataxia and give rise to feelings of pleasure (and/or worsen psychotic symptoms in vulnerable individuals). See Table 8.7.

Alcohol can cause or worsen psychotic symptoms by increasing dopamine release in mesolimbic pathways. The effect of antipsychotic drugs may be competitively antagonised, rendering them less effective.

Electrolyte disturbances secondary to alcohol-related dehydration can be exacerbated by other drugs that cause electrolyte disturbances such as diuretics.

Note that heavy alcohol consumption can lead to hypoglycaemia in people with diabetes who take insulin or oral hypoglycaemics. Theoretically there is an increased risk of lactic acidosis in patients who take metformin with alcohol. Alcohol can also increase blood pressure.

Chronic drinkers are particularly susceptible to the gastrointestinal irritant effects of aspirin and NSAIDs.

Table 8.7 Pharmacodynamic interactions with alcohol

Table 8.8 Psychotropic drugs: choice in patients who continue to drink

Note: in the presence of pharmacokinetic interactions, pharmacodynamic interactions will be more marked. For example, in a chronic heavy drinker who is sober, enzyme induction will increase the metabolism of diazepam which may lead to increased levels of anxiety (treatment failure). If the same patient becomes intoxicated with alcohol, the metabolism of diazepam will be greatly reduced as it will have to compete with alcohol for the metabolic capacity of CYP3A4. Plasma levels of alcohol and diazepam will rise (toxicity). As both alcohol and diazepam are sedative (via GABA affinity), loss of consciousness and respiratory depression may occur.

Note: be aware of the possibility of hepatic failure or reduced hepatic function in chronic alcohol misusers. See section on 'Hepatic impairment' in Chapter 7. Also note risk of hepatic toxicity with some recommended drugs (e.g. valproate). Psychotropic drugs of choice are given in Table 8.8.

References

1. Zakhari S. Overview: how is alcohol metabolized by the body? Alcohol Res Health 2006; 29:245–254.
2. Tanaka E. Toxicological interactions involving psychiatric drugs and alcohol: an update. J Clin Pharm Ther 2003; 28:81–95.
3. Wan Chih T. Alcohol-related drug interactions. Pharmacist's Letter/Prescriber's Letter 2008; 24:240106.
4. Smith RG. An appraisal of potential drug interactions in cigarette smokers and alcohol drinkers. J Am Podiatr Med Assoc 2009; 99:81–88.
5. Salmela KS et al. Respective roles of human cytochrome P-4502E1, 1A2, and 3A4 in the hepatic microsomal ethanol oxidizing system. Alcohol Clin Exp Res 1998; 22:2125–2132.
6. Hamitouche S et al. Ethanol oxidation into acetaldehyde by 16 recombinant human cytochrome P450 isoforms: role of CYP2C isoforms in human liver microsomes. Toxicol Lett 2006; 167:221–230.
7. Stahl SM et al. Essential Psychopharmacology: Neuroscientific Basis and Practical Applications, 3rd edn. Cambridge: Cambridge University Press; 2008.

Further reading

Joint Formulary Committee. BNF 67 March-September 2014 (online). London: Pharmaceutical Press; 2014. http://www.medicinescomplete.com/ mc/bnf/current/

Stockley's Drug Interactions. London: Pharamceutical Press; 2014. https://www.medicinescomplete.com/

Nicotine

The most common method of consuming nicotine is by smoking cigarettes. One-quarter of the general population, 40–50% of those with depression¹ and 70–80% of those with schizophrenia smoke.² Nicotine causes peripheral vasoconstriction, tachycardia and increased blood pressure.³ Smokers are at increased risk of developing cardiovascular disease. People with schizophrenia who smoke are more likely to develop the metabolic syndrome, compared with those who do not smoke.⁴ As well as nicotine, cigarettes also contain tar (a complex mixture of organic molecules, many carcinogenic), a cause of cancers of the respiratory tract, chronic bronchitis and emphysema.⁵ Electronic cigarettes, it is claimed, contain only nicotine, which has very limited toxicity and is not thought to be carcinogenic. E-cigarettes are thus preferred for all smokers, albeit with some reservations in regard to quality control of content and the so-called re-normalisation of smoking.

Nicotine is highly addictive; an effect which may be at least partially genetically determined.⁶ People with mental illness are 2–3 times more likely than the general population to develop and maintain a nicotine addiction.¹ Chronic smoking contributes to the increased morbidity and mortality from respiratory and cardiovascular disease that is seen in this patient group. Nicotine also has psychotropic effects. Smoking can affect the metabolism (and therefore the efficacy and toxicity) of drugs prescribed to treat psychiatric illness.⁷ See section on 'Smoking and psychotropic drugs' in this chapter. Nicotine use may be a gateway to experimenting with other psychoactive substances.

Psychotropic effects

Nicotine is highly lipid-soluble and rapidly enters the brain after inhalation. Nicotine receptors are found on dopaminergic cell bodies and stimulation of these receptors leads to dopamine release.¹ Dopamine release in the limbic system is associated with pleasure: dopamine is the brain's 'reward' neurotransmitter. Nicotine may be used by people with mental health problems as a form of 'self-medication' (e.g. to alleviate the negative symptoms of schizophrenia or antipsychotic-induced extrapyramidal sideeffects [EPS] or for its anxiolytic effect⁸). Drugs that increase the release of dopamine reduce the craving for nicotine. They may also worsen psychotic illness (see the section on 'Nicotine and smoking cessation' in Chapter 6).

Nicotine improves concentration and vigilance.¹ It also enhances the effects of glutamate, acetylcholine and serotonin.⁸

Schizophrenia

Seventy to eighty per cent of people with schizophrenia regularly smoke cigarettes² and this increased tendency to smoke predates the onset of psychiatric symptoms.⁹ Possible explanations are as follows: smoking causes dopamine release, leading to feelings of well-being and a reduction in negative symptoms;⁸ to alleviate some of the side-effects of antipsychotics such as drowsiness and EPS¹ and cognitive slowing;¹⁰ as a means of structuring the day (a behavioural filler); a familial vulnerability¹¹ or as a means of alleviating the deficit in auditory gaiting that is found in schizophrenia.¹²

Nicotine may also improve working memory and attentional deficits.^13–15 Nicotinic receptor agonists may have beneficial effects on neurocognition,^16,17 although none is yet licensed for this purpose. Note though that cholinergic drugs may exacerbate nicotine dependence.¹⁸ A single photon emission computed tomography (SPECT) study has shown that the greater the occupancy of striatal D₂ receptors by antipsychotic drugs, the more likely the patient is to smoke.¹⁹ This may partly explain the clinical observation that smoking cessation may be more achievable when clozapine (a weak dopamine antagonist) is prescribed in place of a conventional antipsychotic. It has been suggested that people with schizophrenia find it particularly difficult to tolerate nicotine withdrawal symptoms.⁷ Switching to nicotine replacement therapy (NRT) or e-cigarettes may thus be a preferred option.²⁰

Depression and anxiety

In 'normal' individuals a moderate consumption of nicotine is associated with pleasure and a decrease in anxiety and feelings of anger.²¹ The mechanism of this anxiolytic effect is not understood. People who suffer from anxiety and/or depression are more likely to smoke^22,23 and find it more difficult to stop.^21,24 This is compounded by the observation that nicotine withdrawal can precipitate or exacerbate depression in those with a history of the illness,²¹ and cigarette smoking may directly increase the risk of symptoms of depression.²⁵ In marked contrast, a recent analysis suggests that stopping smoking actually improves depression and anxiety.²⁶ These contradictory findings are explained by the fact that early withdrawal worsens depression whereas successful cessation improves depression in the longer term.

Patients with depression are at increased risk of cardiovascular disease. By directly causing tachycardia and hypertension,³ nicotine may, in theory, exacerbate this problem. More importantly, smoking is a well known independent risk factor for cardiovascular disease, probably because it hastens athlerosclerosis. A Cochrane review²⁷ suggests smoking cessation is achievable in depressed smokers.

Movement disorders and Parkinson's disease

By increasing dopaminergic neurotransmission, nicotine provides a protective effect against both drug-induced EPS and idiopathic Parkinson's disease. Smokers are less likely to suffer from antipsychotic-induced movement disorders than non-smokers¹ and use anticholinergics less often.⁷ Parkinson's disease occurs less frequently in smokers than in non-smokers and the onset of clinical symptoms is delayed.^1,28 This may reflect the inverse association between Parkinson's disease and sensation seeking behavioural traits, rather than a direct effect of nicotine.²⁹

Drug interactions

Polycyclic hydrocarbons in cigarette smoke are known to stimulate the hepatic microsomal enzyme system, particularly P4501A2,⁸ the enzyme responsible for the metabolism of many psychotropic drugs. Smoking can lower the blood levels of some drugs by up to 50%.⁸ This can affect both efficacy and side-effects and needs to be taken into account when making clinical decisions. The drugs most likely to be affected are: clozapine,³⁰ fluphenazine, haloperidol, chlorpromazine, olanzapine, many tricyclic antidepressants, mirtazapine, fluvoxamine and propranolol. See section on 'Smoking and psychotropic drugs' in this chapter.

Withdrawal symptoms⁷

Withdrawal symptoms occur within 6–12 hours of stopping smoking and include intense craving, depressed mood, insomnia, anxiety, restlessness, irritability, difficulty in concentrating and increased appetite. Nicotine withdrawal can be confused with depression, anxiety, sleep disorders and mania. Withdrawal can also exacerbate the symptoms of schizophrenia.

Smoking cessation

See section on 'Nicotine and smoking cessation' in Chapter 6.

References

1. Goff DC et al. Cigarette smoking in schizophrenia: relationship to psychopathology and medication side effects. Am J Psychiatry 1992; 149:1189–1194.
2. Winterer G. Why do patients with schizophrenia smoke? Curr Opin Psychiatry 2010; 23:112–119.
3. Benowitz NL et al. Cardiovascular effects of nasal and transdermal nicotine and cigarette smoking. Hypertension 2002; 39:1107–1112.
4. Yevtushenko OO et al. Influence of 5-HT2C receptor and leptin gene polymorphisms, smoking and drug treatment on metabolic disturbances in patients with schizophrenia. Br J Psychiatry 2008; 192:424–428.
5. Anderson JE et al. Treating tobacco use and dependence: an evidence-based clinical practice guideline for tobacco cessation. Chest 2002; 121:932–941.
6. Berrettini W. Nicotine addiction. Am J Psychiatry 2008; 165:1089–1092.
7. Ziedonis DM et al. Schizophrenia and nicotine use: report of a pilot smoking cessation program and review of neurobiological and clinical issues. Schizophr Bull 1997; 23:247–254.
8. Lyon ER. A review of the effects of nicotine on schizophrenia and antipsychotic medications. Psychiatr Serv 1999; 50:1346–1350.
9. Weiser M et al. Higher rates of cigarette smoking in male adolescents before the onset of schizophrenia: a historical-prospective cohort study. Am J Psychiatry 2004; 161:1219–1223.
10. Harris JG et al. Effects of nicotine on cognitive deficits in schizophrenia. Neuropsychopharmacology 2004; 29:1378–1385.
11. Ferchiou A et al. Exploring the relationships between tobacco smoking and schizophrenia in first-degree relatives. Psychiatry Res 2012; 200:674–678.
12. McEvoy JP et al. Smoking and therapeutic response to clozapine in patients with schizophrenia. Biol Psychiatry 1999; 46:125–129.
13. Jacobsen LK et al. Nicotine effects on brain function and functional connectivity in schizophrenia. Biol Psychiatry 2004; 55:850–858.
14. Sacco KA et al. Effects of cigarette smoking on spatial working memory and attentional deficits in schizophrenia: involvement of nicotinic receptor mechanisms. Arch Gen Psychiatry 2005; 62:649–659.
15. Smith RC et al. Effects of nicotine nasal spray on cognitive function in schizophrenia. Neuropsychopharmacology 2006; 31:637–643.
16. Olincy A et al. Proof-of-concept trial of an alpha7 nicotinic agonist in schizophrenia. Arch Gen Psychiatry 2006; 63:630–638.
17. Lieberman JA et al. Cholinergic agonists as novel treatments for schizophrenia: the promise of rational drug development for psychiatry. Am J Psychiatry 2008; 165:931–936.
18. Kelly DL et al. Lack of beneficial galantamine effect for smoking behavior: a double-blind randomized trial in people with schizophrenia. Schizophr Res 2008; 103:161–168.
19. de Haan L et al. Occupancy of dopamine D2 receptors by antipsychotic drugs is related to nicotine addiction in young patients with schizophrenia. Psychopharmacology 2006; 183:500–505.
20. Caponnetto P et al. Impact of an electronic cigarette on smoking reduction and cessation in schizophrenic smokers: a prospective 12-month pilot study. Int J Environ Res Public Health 2013; 10:446–461.
21. Glassman AH. Cigarette smoking: implications for psychiatric illness. Am J Psychiatry 1993; 150:546–553.
22. Nunes SO et al. The shared role of oxidative stress and inflammation in major depressive disorder and nicotine dependence. Neurosci Biobehav Rev 2013; 37:1336–1345.
23. Tsuang MT et al. Genetics of smoking and depression. Hum Genet 2012; 131:905–915.
24. Wilhelm K et al. Clinical aspects of nicotine dependence and depression. Med Today 2004; 5:40–47.
25. Boden JM et al. Cigarette smoking and depression: tests of causal linkages using a longitudinal birth cohort. Br J Psychiatry 2010; 196:440–446.
26. Taylor G et al. Change in mental health after smoking cessation: systematic review and meta-analysis. BMJ 2014; 348:g1151.
27. van der Meer RM et al. Smoking cessation interventions for smokers with current or past depression. Cochrane Database Syst Rev 2013; 8: CD006102.
28. Scott WK et al. Family-based case-control study of cigarette smoking and Parkinson disease. Neurology 2005; 64:442–447.
29. Evans AH et al. Relationship between impulsive sensation seeking traits, smoking, alcohol and caffeine intake, and Parkinson's disease. J Neurol Neurosurg Psychiatry 2006; 77:317–321.
30. Derenne JL et al. Clozapine toxicity associated with smoking cessation: case report. Am J Ther 2005; 12:469–471.

Further reading

Aguilar MC et al. Nicotine dependence and symptoms in schizophrenia: naturalistic study of complex interactions. Br J Psychiatry 2005;186:215–21.

Ziedonis D et al. Tobacco use and cessation in psychiatric disorders: National Institute of Mental Health report. Nicotine Tob Res 2008; 10:1691–1715.

Smoking and psychotropic drugs

Tobacco smoke contains polycyclic aromatic hydrocarbons that induce (increase the activity of) certain hepatic enzymes (CYP1A2 in particular).¹ For some drugs used in psychiatry, smoking significantly reduces drug plasma levels and higher doses are required than in non-smokers.

When people stop smoking, enzyme activity reduces over a week or so. (Nicotine replacement or use of electronic cigarettes has no effect on this process.) Plasma levels of affected drugs will then rise, sometimes substantially. Dose reduction will usually be necessary. If smoking is re-started, enzyme activity increases, plasma levels fall and dose increases are then required. The process is complicated and effects are difficult to predict. Of course, few people manage to give up smoking completely, so additional complexity is introduced by intermittent smoking and repeated attempts at stopping completely. Close monitoring of plasma levels (where useful), clinical progress and adverse effect severity are essential.

Table 8.9 gives details of psychotropic drugs known to be affected by smoking status.

Table 8.9 Psychotropic drugs affected by smoking status

References

1. Kroon LA. Drug interactions with smoking. Am J Health Syst Pharm 2007; 64:1917–1921.
2. Servier Laboratories Limited. Summary of Product Characteristics. Valdoxan. 2013. http://www.medicines.org.uk/emc/medicine/21830/SPC/ Valdoxan/
3. Desai HD et al. Smoking in patients receiving psychotropic medications: a pharmacokinetic perspective. CNS Drugs 2001; 15:469–494.
4. Miller LG. Recent developments in the study of the effects of cigarette smoking on clinical pharmacokinetics and clinical pharmacodynamics. Clin Pharmacokinet 1989; 17:90–108.
5. Goff DC et al. Cigarette smoking in schizophrenia: relationship to psychopathology and medication side effects. Am J Psychiatry 1992; 149:1189–1194.
6. Haring C et al. Influence of patient-related variables on clozapine plasma levels. Am J Psychiatry 1990; 147:1471–1475.
7. Haring C et al. Dose-related plasma levels of clozapine: influence of smoking behaviour, sex and age. Psychopharmacology 1989; 99 Suppl:S38–S40.
8. Diaz FJ et al. Estimating the size of the effects of co-medications on plasma clozapine concentrations using a model that controls for clozapine doses and confounding variables. Pharmacopsychiatry 2008; 41:81–91.
9. Murayama-Sung L et al. The impact of hospital smoking ban on clozapine and norclozapine levels. J Clin Psychopharmacol 2011; 31:124–126.
10. Cormac I et al. A retrospective evaluation of the impact of total smoking cessation on psychiatric inpatients taking clozapine. Acta Psychiatr Scand 2010; 121:393–397.
11. Fric M et al. The influence of smoking on the serum level of duloxetine. Pharmacopsychiatry 2008; 41:151–155.
12. Ereshefsky L et al. Effects of smoking on fluphenazine clearance in psychiatric inpatients. Biol Psychiatry 1985; 20:329–332.
13. Spigset O et al. Effect of cigarette smoking on fluvoxamine pharmacokinetics in humans. Clin Pharmacol Ther 1995; 58:399–403.
14. Jann MW et al. Effects of smoking on haloperidol and reduced haloperidol plasma concentrations and haloperidol clearance. Psychopharmacology 1986; 90:468–470.
15. Shimoda K et al. Lower plasma levels of haloperidol in smoking than in nonsmoking schizophrenic patients. Ther Drug Monit 1999; 21:293–296.
16. Grasmader K et al. Population pharmacokinetic analysis of mirtazapine. Eur J Clin Pharmacol 2004; 60:473–480.
17. Carrillo JA et al. Role of the smoking-induced cytochrome P450 (CYP)1A2 and polymorphic CYP2D6 in steady-state concentration of olanzapine. J Clin Psychopharmacol 2003; 23:119–127.
18. Gex-Fabry M et al. Therapeutic drug monitoring of olanzapine: the combined effect of age, gender, smoking, and comedication. Ther Drug Monit 2003; 25:46–53.
19. Bigos KL et al. Sex, race, and smoking impact olanzapine exposure. J Clin Pharmacol 2008; 48:157–165.
20. Lowe EJ et al. Impact of tobacco smoking cessation on stable clozapine or olanzapine treatment. Ann Pharmacother 2010; 44:727–732.
21. Jann MW et al. Clinical pharmacokinetics of the depot antipsychotics. Clin Pharmacokinet 1985; 10:315–333.
22. Jorgensen A et al. Zuclopenthixol decanoate in schizophrenia: serum levels and clinical state. Psychopharmacology 1985; 87:364–367.

Caffeine

Caffeine is probably the most popular psychoactive substance in the world. Mean daily consumption in the UK is 350–620 mg.¹ A quarter of the general population and half of those with psychiatric illness regularly consume over 500 mg caffeine/day.² Consumption of caffeine should be routinely discussed with an individual to assess its effect on their symptoms and presentation.³ In particular, caffeine withdrawal can have a marked effect on mental and physical health. See Table 8.10 for the caffeine content of various drinks.

Chocolate also contains caffeine. Martindale lists over 600 medicines that contain caffeine.⁴ Most are available without prescription and are marketed as analgesics or appetite suppressants.

General effects of caffeine

• Acute use can increase systolic and diastolic BP by up to 10 mmHg; for up to 4 hours.³ Chronic moderate use probably has little effect on BP.⁵
• May enhance reinforcing effects of nicotine and possibly other drugs of abuse.^4,6
• Caffeine has de novo psychotropic effects (Table 8.11), may worsen existing psychiatric illness, and interact with psychotropic drugs.
• Caffeine is an antagonist at adenosine A₁ and A_2A receptors, thus stimulating dopamine pathways.

Pharmacokinetics

• Absorption
• rapid after oral administration, especially in liquid form
• half-life of 2.5–4.5 hours.
• Metabolism
• metabolised by CYP1A2, a hepatic cytochrome enzyme that exhibits genetic polymorphism, which may partially account for the large inter-individual differences that are seen in the ability to tolerate caffeine.¹⁰ Note that CYP1A2 is induced by smoking and inhibited by a number of drugs such as fluvoxamine
• metabolic pathways also become saturated at higher doses.¹¹

Table 8.10 Caffeine content of drinks

Table 8.11 Psychotropic effects of caffeine

• Interactions
• the potential effects of caffeine on the metabolism of other drugs, as well as the potential to induce a caffeine-withdrawal syndrome, should always be considered before substituting caffeine-free drinks (Table 8.12)
• caffeine competitively inhibits CYP1A2. Plasma levels of some drugs may be reduced if caffeine is withdrawn.

Caffeine intoxication

The Diagnostic and Statistical Manual of Mental Disorders DSM-V¹⁶ defines caffeine intoxication as the recent consumption of caffeine, usually in excess of 250 mg accompanied by five or more of the symptoms shown in Box 8.2.

In caffeine intoxication, these symptoms cause significant distress or impairment in social, occupational or other important areas of functioning and are not due to a general medical condition or better accounted for by another mental disorder (e.g. an anxiety disorder).

Caffeine abuse or dependence as a clinical syndrome has been reported³ and Caffeine Use Disorder and Caffeine Withdrawal are both DSM-V diagnoses.

Energy drinks

So called energy drinks contain large amounts of caffeine along with sugar, vitamins and a number of other ingredients such as guarana. There is some evidence that these drinks can improve attention and short-term memory.¹⁷ Marketing is targeted at adolescents and young adults, some of whom consume large volumes of these drinks, and seem to be particularly vulnerable to developing signs and symptoms of caffeine intoxication. Symptoms of anxiety and depression, frank suicidal behaviour and seizures have been associated with use of these products by young people.^18–20

Table 8.12 Interactions of caffeine

Schizophrenia

• Patients with schizophrenia often consume large amounts of caffeine-containing drinks¹ and they are twice as likely as controls to consume > 200 mg caffeine/day.⁷
• This may be to relieve dry mouth (as a side-effect of antipsychotic drugs), for the stimulant effects of caffeine (to relieve dysphoria/sedation/negative symptoms)⁷ or simply because coffee/tea drinking structures the day or relieves boredom.
• Schizophrenia may increase sensitivity to drug related cues.⁷
• Large doses of caffeine can worsen psychotic symptoms⁷ (in particular elation and conceptual disorganisation) and result in the prescription of larger doses of antipsychotic drugs.
• The removal of caffeine from the diets of chronically disturbed (challenging behaviour) patients, may lead to decreased levels of hostility, irritability and suspiciousness²¹ and may be of benefit in clozapine resistant schizophrenia,²² although this may not hold true in less disturbed populations.²³

Mood disorders

• Caffeine may elevate mood through increasing noradrenaline release²⁴ and modest caffeine consumption may protect against depression in those who do not have a preexisting mood disorder.²⁵
• People with mood disorders are more likely to consume caffeine, particularly when depressed.^13,26
• Depressed patients may be more sensitive to the anxiogenic effects of caffeine.^27,28
• Excessive consumption of caffeine may precipitate mania.^28–30
• Caffeine can increase cortisol secretion (gives a false positive in the dexamethasonesuppression test),³¹ increase seizure length during ECT³² and increase the clearance of lithium by promoting dieresis.³³

Anxiety disorders

• Increases vigilance, decreases reaction times, increases sleep latency and worsens subjective estimates of sleep quality, effects that may be more marked in poor metabolisers.
• May precipitate or worsen generalised anxiety and panic attacks;³⁴ vulnerability to these effects may be genetically determined.⁶
• Effects are so marked that caffeine intoxication should always be considered when patients complain of anxiety symptoms or insomnia.
• Symptoms may diminish considerably or even abate completely if caffeine is avoided.³⁵

In summary, caffeine:

• is present in high quantities in coffee and some soft drinks, particularly energy drinks
• may worsen psychosis and anxiety; young people may be particularly vulnerable
• can increase plasma clozapine levels
• may induce intoxication which is characterised by psychomotor agitation and rambling speech
• may be associated with toxicity when co-administered with CYP1A2 inhibitors such as fluvoxamine
• can enhance the reinforcing effects of nicotine and possibly other drugs of abuse.

References

1. Rihs M et al. Caffeine consumption in hospitalized psychiatric patients. Eur Arch Psychiatry Clin Neurosci 1996; 246:83–92.
2. Clementz GL et al. Psychotropic effects of caffeine. Am Fam Physician 1988; 37:167–172.
3. Ogawa N et al. Clinical importance of caffeine dependence and abuse. Psychiatry Clin Neurosci 2007; 61:263–268.
4. Martindale: The Complete Drug Reference. London: Pharmaceutical Press; 2014. https://www.medicinescomplete.com/
5. O'Keefe JH et al. Effects of habitual coffee consumption on cardiometabolic disease, cardiovascular health, and all-cause mortality. J Am Coll Cardiol 2013; 62:1043–1051.
6. Bergin JE et al. Common psychiatric disorders and caffeine use, tolerance, and withdrawal: an examination of shared genetic and environmental effects. Twin Res Hum Genet 2012; 15:473–482.
7. Adolfo AB et al. Effects of smoking cues on caffeine urges in heavy smokers and caffeine consumers with and without schizophrenia. Schizophr Res 2009; 107:192–197.
8. Sawynok J. Pharmacological rationale for the clinical use of caffeine. Drugs 1995; 49:37–50.
9. Silverman K et al. Withdrawal syndrome after the double-blind cessation of caffeine consumption. N Engl J Med 1992; 327:1109–1114.
10. Butler MA et al. Determination of CYP1A2 and NAT2 phenotypes in human populations by analysis of caffeine urinary metabolites. Pharmacogenetics 1992; 2:116–127.
11. Kaplan GB et al. Dose-dependent pharmacokinetics and psychomotor effects of caffeine in humans. J Clin Pharmacol 1997; 37:693–703.
12. Stockley's Drug Interactions. London: Pharamceutical Press; 2014. https://www.medicinescomplete.com/
13. Baethge C et al. Coffee and cigarette use: association with suicidal acts in 352 Sardinian bipolar disorder patients. Bipolar Disord 2009; 11:494–503.
14. Carrillo JA et al. Effects of caffeine withdrawal from the diet on the metabolism of clozapine in schizophrenic patients. J Clin Psychopharmacol 1998; 18:311–316.
15. Shioda K et al. Possible serotonin syndrome arising from an interaction between caffeine and serotonergic antidepressants. Hum Psychopharmacol 2004; 19:353–354.
16. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th edn (DSM-5). Arlington, VA: American Psychiatric Association; 2013.
17. Wesnes KA et al. An evaluation of the cognitive and mood effects of an energy shot over a 6 h period in volunteers: a randomized, doubleblind, placebo controlled, cross-over study. Appetite 2013; 67:105–113.
18. Szpak A et al. A case of acute suicidality following excessive caffeine intake. J Psychopharmacol 2012; 26:1502–1510.
19. Trapp GS et al. Energy drink consumption among young Australian adults: associations with alcohol and illicit drug use. Drug Alcohol Depend 2014; 134:30–37.
20. Pennington N et al. Energy drinks: a new health hazard for adolescents. J Sch Nurs 2010; 26:352–359.
21. De Freitas B et al. Effects of caffeine in chronic psychiatric patients. Am J Psychiatry 1979; 136:1337–1338.
22. Dratcu L et al. Clozapine-resistant psychosis, smoking, and caffeine: managing the neglected effects of substances that our patients consume every day. Am J Ther 2007; 14:314–318.
23. Koczapski A et al. Effects of caffeine on behavior of schizophrenic inpatients. Schizophr Bull 1989; 15:339–344.
24. Achor MB et al. Diet aids, mania, and affective illness. Am J Psychiatry 1981; 138:392.
25. Lucas M et al. Coffee, caffeine, and risk of depression among women. Arch Intern Med 2011; 171:1571–1578.
26. Maremmani I et al. Are "social drugs" (tobacco, coffee and chocolate) related to the bipolar spectrum? J Affect Disord 2011; 133:227–233.
27. Lee MA et al. Anxiogenic effects of caffeine on panic and depressed patients. Am J Psychiatry 1988; 145:632–635.
28. Rizkallah E et al. Could the use of energy drinks induce manic or depressive relapse among abstinent substance use disorder patients with comorbid bipolar spectrum disorder? Bipolar Disord 2011; 13:578–580.
29. Machado-Vieira R et al. Mania associated with an energy drink: the possible role of caffeine, taurine, and inositol. Can J Psychiatry 2001; 46:454–455.
30. Ogawa N et al. Secondary mania caused by caffeine. Gen Hosp Psychiatry 2003; 25:138–139.
31. Uhde TW et al. Caffeine-induced escape from dexamethasone suppression. Arch Gen Psychiatry 1985; 42:737–738.
32. Cantu TG et al. Caffeine in electroconvulsive therapy. Ann Pharmacother 1991; 25:1079–1080.
33. Mester R et al. Caffeine withdrawal increases lithium blood levels. Biol Psychiatry 1995; 37:348–350.
34. Bruce MS. The anxiogenic effects of caffeine. Postgrad Med J 1990; 66 Suppl 2:S18–S24.
35. Bruce MS et al. Caffeine abstention in the management of anxiety disorders. Psychol Med 1989; 19:211–214.

Further reading

Caffeine: In AHFS Drug Information. American Society of Health Care Pharmacists. http://www.medicinescomplete.com

Paton C, Beer D. Caffeine: the forgotten variable. Int J Psychiatry Clin Pract 2002; 5: 231–236.

Complementary therapies

Complementary therapies are those used alongside orthodox treatments with the aim of providing psychological and emotional support through the relief of symptoms. A wide range of treatments are available, most with limited or no scientific support. These therapies do not change or develop over time, there being almost no research aimed at determining best practice. Whenever an alternative treatment is shown to be active, it usually becomes part of mainstream practice.

A large proportion of the population currently use or have recently used complementary therapies (CTs).¹ Most users suffer from psychiatric conditions.^2,3 As health professionals are rarely consulted before purchase, a diagnosis is often not made and efficacy and side-effects are not monitored. The majority of those who use CTs are also taking conventional medicines and many people use more than one CT simultaneously.⁴ Many do not tell their doctor.⁵ The public associate natural products with safety and may be unwilling to report possible side-effects.⁶ Herbal medicines, in particular, can be toxic as they contain pharmacologically active substances.⁷ Many conventional drugs prescribed today were originally derived from plants. These include medicines as diverse as aspirin, digoxin and the vinca alkaloids used in cancer chemotherapy. Herbal medicines such as St John's wort, Ginkgo biloba, Yokukansan and Valerian are increasingly used as self-medication for psychiatric and neurodegenerative illnesses.^3,8–13

Few CTs have been subject to randomised controlled trials, so efficacy is largely unproven. For some, Cochrane Reviews exist, but none support their use. These include the use of Chinese herbal medicine as an adjunct to antipsychotics in schizophrenia (promising, more evidence required)¹⁴ aromatherapy for behavioural problems in dementia (insufficient evidence, but worth further study)^15,16 and hypnosis for schizophrenia (insufficient evidence, but worth further study).¹⁷ Several complementary therapies are thought to be worthy of further study in the adjunctive management of substance misuse.¹⁸ There is some preliminary, limited support for aromatherapy as an adjunct to conventional treatments in a range of psychiatric conditions.¹⁹ Folic Acid²⁰ and Vitamin D²¹ have been used in depression.

There is little systematic monitoring of side-effects caused by CTs, so safety is unknown. There are an increasing number of published case reports of significant drug–herb interactions;²² these include ginkgo and aspirin or warfarin leading to increased bleeding, ginkgo and trazodone leading to coma, and ginseng and phenelzine leading to mania.^23,24 The wide range of drug interactions with St John's wort are outlined in the section 'Drug interactions with antidepressants' in Chapter 4.

Some herbs are known to be very toxic.^25,26 During consultation with patients or in the process of medicine reconciliation, the use of any specific complementary therapies should be explored and reviewed.

Whatever the perceived 'evidence base' for the use of complementary therapies, the feelings of autonomy engendered by (apparently) taking control of one's own illness and treatment can result in important psychological benefits irrespective of any direct therapeutic benefits of the CT; the placebo effect is likely to be important here. (see section on 'Observations on the placebo effect in mental illness' in this chapter.) There are many different complementary therapies, the most popular being homeopathy and herbal medicine with its branches of Bach's flower remedies, and Chinese and Ayurvedic medicine. Non-drug therapies such as acupuncture and osteopathy are also popular. Aromatherapy is usually considered to be a non-pharmacological treatment but this may not be the case.²⁷ Physical exercise²⁸ and spirituality²⁹ have also been suggested.

Table 8.13 An introduction to complementary therapies

To master one CT can sometimes take years of study. Therefore, to ensure safe and effective treatment, any referrals should be to a qualified practitioner with the Complementary and Natural Healthcare Council.³⁰

Be aware, nonetheless, that scientific support for most complementary medicine is minimal and 'qualification' to practise may entail little in the way of examination or regulation. Moreover, much of what is taught and learned is palpable nonsense. The majority of doctors and pharmacists have no qualifications or specific training in CTs. Table 8.13 gives a brief introduction. Further reading is strongly recommended.

References

1. Posadzki P et al. Prevalence of use of complementary and alternative medicine (CAM) by patients/consumers in the UK: systematic review of surveys. Clin Med 2013; 13:126–131.
2. Barnes J et al. Herbal Medicines, 3rd edn. London: Pharmaceutical Press; 2007.
3. Werneke U. Complementary medicines in mental health. Evid Based Ment Health 2009; 12:1–4.
4. Fischer FH et al. High prevalence but limited evidence in complementary and alternative medicine: guidelines for future research. BMC Complementary and Alternative Medicine 2014; 14:46.
5. Robinson A et al. Disclosure of CAM use to medical practitioners: a review of qualitative and quantitative studies. Complement Ther Med 2004; 12:90–98.
6. Barnes J et al. Different standards for reporting ADRs to herbal remedies and conventional OTC medicines: face-to-face interviews with 515 users of herbal remedies. Br J Clin Pharmacol 1998; 45:496–500.
7. Medicines and Healthcare Products Regulatory Agency. Public health risk with herbal medicines: an overview. London: MHRA; 2008. http://www.mhra.gov.uk/home/groups/es-herbal/documents/websiteresources/con023163.pdf
8. van der Watt G et al. Complementary and alternative medicine in the treatment of anxiety and depression. Curr Opin Psychiatry 2008; 21:37–42.
9. Andreescu C et al. Complementary and alternative medicine in the treatment of bipolar disorder: a review of the evidence. J Affect Disord 2008; 110:16–26.
10. Singh V et al. Review and meta-analysis of usage of ginkgo as an adjunct therapy in chronic schizophrenia. Int J Neuropsychopharmacol 2010; 13:257–271.
11. Birks J et al. Ginkgo biloba for cognitive impairment and dementia. Cochrane Database Syst Rev 2009; CD003120.
12. Miyaoka T et al. Efficacy and safety of yokukansan (TJ-54) for treatment-resistant schizophrenia: a randomised placebo-controlled trial. Eur Neuropsychopharmacol 2013; 23 Suppl 2:S476.
13. Matsuda Y et al. Yokukansan in the treatment of behavioral and psychological symptoms of dementia: a systematic review and meta-analysis of randomized controlled trials. Hum Psychopharmacol 2013; 28:80–86.
14. Rathbone J et al. Chinese herbal medicine for schizophrenia: Cochrane systematic review of randomised trials. Br J Psychiatry 2007; 190:379–384.
15. Thorgrimsen L et al. Aroma therapy for dementia. Cochrane Database Syst Rev 2003; CD003150.
16. Fung JK et al. A systematic review of the use of aromatherapy in treatment of behavioral problems in dementia. Geriatr Gerontol Int 2012; 12:372–382.
17. Izquierdo de SA et al. Hypnosis for schizophrenia. Cochrane Database Syst Rev 2007; CD004160.
18. Dean AJ. Natural and complementary therapies for substance use disorders. Curr Opin Psychiatry 2005; 18:271–276.
19. Perry N et al. Aromatherapy in the management of psychiatric disorders: clinical and neuropharmacological perspectives. CNS Drugs 2006; 20:257–280.
20. Lazarou C et al. The role of folic acid in prevention and treatment of depression: an overview of existing evidence and implications for practice. Complement Ther Clin Pract 2010; 16:161–166.
21. Li G et al. Efficacy of vitamin D supplementation in depression in adults: a systematic review. J Clin Endocrinol Metab 2013;jc20133450.
22. Hu Z et al. Herb-drug interactions: a literature review. Drugs 2005; 65:1239–1282.
23. Chen XW et al. Clinical herbal interactions with conventional drugs: from molecules to maladies. Curr Med Chem 2011; 18:4836–4850.
24. Izzo AA et al. Interactions between herbal medicines and prescribed drugs: a systematic review. Drugs 2001; 61:2163–2175.
25. Ernst E. Serious psychiatric and neurological adverse effects of herbal medicines: a systematic review. Acta Psychiatr Scand 2003; 108:83–91.
26. De Smet PA. Health risks of herbal remedies: an update. Clin Pharmacol Ther 2004; 76:1–17.
27. Nguyen QA et al. The use of aromatherapy to treat behavioural problems in dementia. Int J Geriatr Psychiatry 2008; 23:337–346.
28. Cooney GM et al. Exercise for depression. Cochrane Database Syst Rev 2013; 9: CD004366.
29. Royal College of Psychiatrists' Spirituality and Psychiatry Special Interest Group Executive Committee. Spirituality and mental health. 2013. http://www.rcpsych.ac.uk/healthadvice/treatmentswellbeing/spirituality.aspx
30. Complementary and Natural Healthcare Council. What should I look for when choosing a complementary therapist? 2014. http://www.cnhc. org.uk
31. NHS Centre for Reviews and Dissemination. Homeopathy. Effect Health Care Bull 2002; 7:1–12.
32. Davidson JR et al. Homeopathic treatments in psychiatry: a systematic review of randomized placebo-controlled studies. J Clin Psychiatry 2011; 72:795–805.
33. Ernst E et al. Oxford Handbook of Complementary Medicine. Oxford: Oxford University Press; 2008.

Further reading

Rethink Mental Illness. Complementary Therapies. 2012. http://www.rethink.org/

Ernst E. Assessments of complementary and alternative medicine: the clinical guidelines from NICE. Int J Clin Pract 2010; 64:1350–1358.

Enhancing medication adherence

Recommendations made in clinical guidelines regarding the use of medicines are based on evidence from clinical trials supplemented by clinicians' opinions of the balance between the potential benefits and potential risks of treatment. In clinical practice, however, a range of patient-related factors such as insight, health beliefs and the perceived efficacy and tolerability of treatment, influence whether medication is taken, and if so, for how long.

The patient and prescriber should agree jointly on the goals of treatment and how these can be reached. Sticking to this mutually agreed plan is termed concordance or adherence; non-adherence indicates that the treatment plan should be renegotiated, and not that the patient is at fault.

How common is non-adherence?

Reviews of adherence generally conclude that approximately 50% of people do not take their medication as prescribed, and that this proportion is similar across chronic physical and mental disorders.¹ This, however, may be an over-simplification in that it is probable that only a very small proportion of patients are fully adherent, the majority are partially adherent to varying degrees, and a few never take any medication at all of their own volition.²

There is some variation in adherence rates both over time and across settings. For example, ten days after discharge from hospital, up to 25% of patients with schizophrenia are partially or completely non-adherent and this figure rises to 50% at one year and 75% by 2 years.³ In some mental healthcare settings the rate of non-adherence may be up to 90%.⁴

Poor adherence to medication is a major risk factor for poor outcomes including relapse in people with schizophrenia,^5–7 bipolar disorder⁸ and depression.^9,10 Wider health benefits are also lost. For example, compared with depressed patients who take an antidepressant, those who do not have a 20% increased risk of an incident myocardial infarction.¹⁰ As a rule of thumb, the lower the amount of prescribed medication that is taken, the poorer the outcome. There is no evidence that newer (presumed better tolerated) medicines are consistently associated with increased adherence.²

According to the World Health Organisation 'increasing the effectiveness of adherence interventions may have far greater impact on the health of the population than any improvements in specific medical treatments'; it has therefore been suggested that non-adherence should be a diagnosable condition for which active interventions are provided.¹¹ Indeed, analyses of data collected as part of the national confidential inquiry into suicide and homicide by people with mental illness, revealed that healthcare providers that had a policy in place regarding how to manage patients who are not taking their medication as prescribed, had 20% fewer suicides than providers that did not have such a policy.¹²

Not surprisingly, non-adherence is known to be more common when the patient disagrees with the need for treatment, the medication regimen is complex, or the patient perceives the side-effects of treatment to be unacceptable.⁹ Adherence may also therefore be medication specific, where some medicines are taken regularly, others intermittently and others not at all. Notably, half of those who stop treatment don't tell their doctor. Psychiatrists generally prefer to use direct questioning over the use of more intrusive/ objective methods of assessing adherence,¹³ and so partial or non-adherence may go undetected.

Why don't people take medication?

Non-adherence can be intentional (sometimes termed 'intelligent' non-adherence) or unintentional or a mixture of both. Most non-adherence is intentional. Individual influences (which can change in any given patient over time) include the following factors.

• Illness-related factors such as denial of illness, specific symptoms such as grandiose or persecutory thoughts or delusions, or the impact of illness on lifestyle (e.g. cognitive deficits, disorganisation).
• Treatment-related factors such as the drug being perceived not to be effective or the sideeffects intolerable; akathisia, weight gain and sexual dysfunction feature prominently here.
• Clinician-related factors such as not feeling listened to or consulted, perceiving the clinician as authoritative or dismissive, being given a poor explanation of treatment or having infrequent contact.
• Patient-related factors such as personal beliefs about illness, denial of illness/or lack of insight, perception of illness severity, being young and male, having co-morbid personality disorder(s) and/or substance misuse, personal beliefs about treatment such as concerns about dependency, concerns about long-term side-effects, a lack of knowledge about treatment, misunderstanding instructions or simply forgetting. Also, up to 25% of people with schizophrenia report missing their psychotic experiences,¹⁴ when effectively treated.
• Environmental and cultural factors such as the family's beliefs about illness and treatment, religious beliefs and peer pressure.

NICE (2009)¹⁵ recommend that, as long as the patient has capacity to consent, their right not to take medication should be respected. If the prescriber considers that this decision may have an adverse effect, the reasons for the patient's decision and the prescriber's concerns should be recorded.

Assessing attitudes to medication

A number of rating scales and checklists are available that help to guide and structure discussion around attitudes to medication. The most widely used is the Drug Attitude Inventory (DAI)¹⁶ which consists of a mix of positive and negative statements about medication; 30 statements in its full form and 10 in its abbreviated form. It is designed to be completed by the patient who simply agrees or disagrees with each statement. The total score is an indicator of the patients overall perception of the balance between the benefits and harms associated with taking medication, and therefore likely adherence. Attitudes to medication as measured using the DAI have been shown to be a useful predictor of compliance over time.¹⁷ Other available checklists include the Rating of Medication Influences Scale (ROMI),¹⁸ the Beliefs about Medicines Questionnaire¹⁹ and the Medication Adherence rating Scale (MARS).⁷

How can you assess adherence?

It is very difficult to be certain about whether or not a patient is taking prescribed medicines; partial and non-adherence are almost always covert until the patient relapses. Clinicians are known to overestimate adherence rates and patients may not openly acknowledge that they are not taking all or any of their medication. NICE recommend that the patient should be asked in a non-judgemental way if they have missed any doses over a specific time period such as the previous week.¹⁵

It is also important to ask the patient about perceived effectiveness and side-effects. More intrusive methods include checks that prescriptions have been collected, asking to see the patient's medication (pill counts) and asking family or carers. For some antipsychotics such as clozapine, olanzapine and risperidone, blood tests can be useful to directly assess plasma levels. It is important to note that plasma levels of these drugs achieved with a fixed dose vary somewhat and it is not possible to accurately determine partial non-adherence (i.e. total non-adherence will be readily revealed but partial and full adherence may be difficult to tell apart). See section on 'Plasma level monitoring' in Chapter 1.

Strategies for improving adherence

Note that few studies specifically recruit non-adherent patients (the refusal rate in such patients is likely to be high) and the specific barriers to adherence are rarely identified. The small effect size seen in many studies may simply be a consequence of this unfocused approach. Where barriers to adherence are identified and targeted interventions delivered, adherence is more likely to improve.²⁰

NICE has reviewed the evidence for adherence over a range of health conditions.¹⁵ They conclude that no specific intervention can be recommended for all patients but, in general, adherence is maximised if:

• the patient is offered information about medicines before the decision is taken to prescribe
• this information is actively discussed, taking into account the patient's understanding and beliefs about diagnosis and treatment
• the information includes the name of the medicine, how it works, the likely benefits and side-effects, and how long it should be continued
• the patient is given the opportunity to be involved in making decisions about prescribed medicines²¹
• at each contact, the patient is asked if they have any concerns about their medicines, and any identified concerns are addressed
• specific to schizophrenia, good social and family support has been shown to have a positive impact on adherence.²¹

NICE further recommend that any intervention that is used to increase adherence should be tailored to overcome the specific difficulties experienced or reported by a patient.

It is essential that the patient's perspective is understood and respected and a treatment plan agreed jointly. The following strategies may help to achieve this:

• explore aspirations for the future and how medication could help, e.g. staying out of hospital or not getting into trouble with the police
• help the patient and carer understand their experiences in a culturally sensitive way that recognises the place of medication in recovery
• work with the patient to elicit and explore the positive and negative things about taking/ not taking medication
• talk through past experiences of medication and exploring which medicines were helpful and less helpful from the patient's perspective
• listen to and acknowledge the concerns of patients and their carers about the use of medication and address any false beliefs
• work collaboratively with the patient to find a medication that the patient perceives to be helpful
• systematically monitor the effectiveness and adverse effects of medication so that the patient feels listened to and respected
• manage adverse effects when they occur. Consider dosage reduction, change of medication, alteration of the timing of doses, or additional medication for side-effects.

Overcoming practical difficulties can also help. Potentially useful strategies include:

• ensuring the patient knows how to obtain medication and is able to do this²²
• keeping medication regimes as simple as possible
• using reminders and prompts, including electronic pill dispensers,²³ telephone followup or mobile phone text messaging^24,25
• maximising engagement with services by introducing patients to their community team before discharge from hospital
• providing support, encouragement and regular planned follow up.

The need to consider multiple strategies tailored to the needs of individual patients is also the conclusion of a Cochrane review that examined medication adherence over a wide range of medical conditions.¹ Almost all of the interventions that were effective in improving adherence in long-term care were complex, and even the most effective interventions did not lead to large improvements in adherence and treatment outcomes. Haynes et al¹ emphasized that there is no evidence that low adherence can be 'cured'; efforts to improve adherence must be maintained for as long as treatment is needed.

'Compliance therapy' for schizophrenia

After early promise in improving insight, adherence, attitudes towards medication and rehospitalisation rates in an inpatient sample,²⁶ further studies of Compliance therapy have failed to replicate this finding. Compliance therapy has been shown to have no advantage over non-specific counselling in either inpatients¹⁷ or outpatients,²⁷ or those who have been clinically unstable in the last year.²⁸

Compliance aids

Compliance aids that contain compartments accommodating up to four doses of multiple medicines each day may be helpful in patients who are clearly motivated to take medication but find this difficult because of disorganisation or cognitive deficits. It should be noted that only 10% of non-compliant patients say that they forgot to take medication²⁹ and that compliance aids are not a substitute for lack of insight or lack of motivation to take medication. Some medicines are unstable when removed from blister packaging and placed in a compliance aid. These include oro-dispersible formulations which are often prescribed for non-adherent patients. In addition, compliance aids are labour intensive (expensive) to fill, it can be difficult to change prescriptions at short notice and the filling of these devices is particularly error-prone.³⁰

Depot antipsychotics

Meta-analyses of clinical trials have shown that the relative and absolute risks of relapse with depot maintenance treatment were 30% and 10% lower respectively, than with oral treatment^31,32 when depots are used. In clinical practice, covert non-adherence is avoided; if the patient defaults from treatment, it will be immediately apparent. NICE recommends that depots are an option in patients who are known to be non-adherent to oral treatment and/or those who prefer this method of administration.³³ Depots are likely to be underused, for example a recent US study found that depot preparations were prescribed for fewer than one in five patients with a recent episode of nonadherence.³⁴ The introduction of so-called atypical depots may allow wider use of these formulations. Wider choice may lead to improved acceptability.

Paying patients to take their medication

There is evidence from controlled trials across a number of disease areas supporting the potential of financial incentives to enhance medication adherence. Paying people to take their medication is extremely controversial, though some clinicians have found this strategy to be successful in high risk patients with psychotic illness.³⁵ An RCT has demonstrated that modest payments improve adherence in patients with psychotic illness.³⁶

References

1. Haynes RB et al. Interventions for enhancing medication adherence. Cochrane Database Syst Rev 2008; CD000011.
2. Masand PS et al. Partial adherence to antipsychotic medication impacts the course of illness in patients with schizophrenia: a review. Prim Care Companion J Clin Psychiatry 2009; 11:147–154.
3. Leucht S et al. Epidemiology, clinical consequences, and psychosocial treatment of nonadherence in schizophrenia. J Clin Psychiatry 2006; 67 Suppl 5:3–8.
4. Cramer JA et al. Compliance with medication regimens for mental and physical disorders. Psychiatr Serv 1998; 49:196–201.
5. Morken G et al. Non-adherence to antipsychotic medication, relapse and rehospitalisation in recent-onset schizophrenia. BMC Psych 2008; 8:32.
6. Knapp M et al. Non-adherence to antipsychotic medication regimens: associations with resource use and costs. Br J Psychiatry 2004; 184:509–516.
7. Jaeger S et al. Adherence styles of schizophrenia patients identified by a latent class analysis of the Medication Adherence Rating Scale (MARS): a six-month follow-up study. Psychiatry Res 2012; 200:83–88.
8. Lang K et al. Predictors of medication nonadherence and hospitalization in Medicaid patients with bipolar I disorder given long-acting or oral antipsychotics. J Med Econ 2011; 14:217–226.
9. Mitchell AJ et al. Why don't patients take their medicine? reasons and solutions in psychiatry. Adv Psychiatr Treat 2007; 13:336–346.
10. Scherrer JF et al. Antidepressant drug compliance: reduced risk of MI and mortality in depressed patients. Am J Med 2011; 124:318–324.
11. Marcum ZA et al. Medication nonadherence: a diagnosable and treatable medical condition. JAMA 2013; 309:2105–2106.
12. Appleby L, Kapur N, Shaw J, Hunt IM, While D, Flynn S et al. National Confidential Inquiry into Suicide and Homicide by People with Mental Illness. 2013. http://www.bbmh.manchester.ac.uk/cmhr/research/centreforsuicideprevention/nci/
13. Vieta E et al. Psychiatrists' perceptions of potential reasons for nonand partial adherence to medication: results of a survey in bipolar disorder from eight European countries. J Affect Disord 2012; 143:125–130.
14. Moritz S et al. Beyond the usual suspects: positive attitudes towards positive symptoms is associated with medication noncompliance in psychosis. Schizophr Bull 2013; 39:917–922.
15. National Institute for Health and Clinical Excellence. Medicines adherence: involving patients in decisions about prescribed medicines and supporting adherence. Clinical Guideline CG76, 2009. http://www.nice.org.uk/
16. Hogan TP et al. A self-report scale predictive of drug compliance in schizophrenics: reliability and discriminative validity. Psychol Med 1983; 13:177–183.
17. O'Donnell C et al. Compliance therapy: a randomised controlled trial in schizophrenia. BMJ 2003; 327:834.
18. Weiden P et al. Rating of medication influences (ROMI) scale in schizophrenia. Schizophr Bull 1994; 20:297–310.
19. Horne R et al. The beliefs about medicines questionnaire: The development and evaluation of a new method for assessing the cognitive representation of medication. Psychol Health 1999; 14:1–24.
20. Staring AB et al. Treatment adherence therapy in people with psychotic disorders: randomised controlled trial. Br J Psychiatry 2010; 197:448–455.
21. Wilder CM et al. Medication preferences and adherence among individuals with severe mental illness and psychiatric advance directives. Psychiatr Serv 2010; 61:380–385.
22. Valenstein M et al. Using a pharmacy-based intervention to improve antipsychotic adherence among patients with serious mental illness. Schizophr Bull 2011; 37:727–736.
23. Velligan D et al. A randomized trial comparing in person and electronic interventions for improving adherence to oral medications in schizophrenia. Schizophr Bull 2013; 39:999–1007.
24. Granholm E et al. Mobile Assessment and Treatment for Schizophrenia (MATS): a pilot trial of an interactive text-messaging intervention for medication adherence, socialization, and auditory hallucinations. Schizophr Bull 2012; 38:414–425.
25. Montes JM et al. A short message service (SMS)-based strategy for enhancing adherence to antipsychotic medication in schizophrenia. Psychiatry Res 2012; 200:89–95.
26. Kemp R et al. Randomised controlled trial of compliance therapy. 18-month follow-up. Br J Psychiatry 1998; 172:413–419.
27. Byerly MJ et al. A trial of compliance therapy in outpatients with schizophrenia or schizoaffective disorder. J Clin Psychiatry 2005; 66:997–1001.
28. Gray R et al. Adherence therapy for people with schizophrenia. European multicentre randomised controlled trial. Br J Psychiatry 2006; 189:508–514.
29. Perkins DO. Predictors of noncompliance in patients with schizophrenia. J Clin Psychiatry 2002; 63:1121–1128.
30. Barber ND et al. Care homes' use of medicines study: prevalence, causes and potential harm of medication errors in care homes for older people. Qual Safety Health Care 2009; 18:341–346.
31. Leucht C et al. Oral versus depot antipsychotic drugs for schizophrenia—a critical systematic review and meta-analysis of randomised longterm trials. Schizophr Res 2011; 127:83–92.
32. Leucht S et al. Antipsychotic drugs versus placebo for relapse prevention in schizophrenia: a systematic review and meta-analysis. Lancet 2012; 379:2063–2071.
33. National Institute for Health and Clinical Excellence. Schizophrenia: core interventions in the treatment and management of schizophrenia in adults in primary and secondary care (update). 2009. http://www.nice.org.uk/
34. West JC et al. Use of depot antipsychotic medications for medication nonadherence in schizophrenia. Schizophr Bull 2008; 34:995–1001.
35. Claassen D et al. Money for medication: financial incentives to improve medication adherence in assertive outreach. Psychiatr Bull 2007; 31:4–7.
36. Priebe S et al. Effectiveness of financial incentives to improve adherence to maintenance treatment with antipsychotics: cluster randomised controlled trial. BMJ 2013; 347:f5847.

Further reading

Barnes TR. Evidence-based guidelines for the pharmacological treatment of schizophrenia: recommendations from the British Association for Psychopharmacology. J Psychopharmacol 2011; 25:567–620.

Driving and psychotropic medicines

Driving a car is important in maintaining independence and freedom. However, no one should drive if their performance is compromised. Everyone has a duty to drive reasonably and all drivers are legally responsible for accidents they cause.¹

Many factors have been shown to affect driving performance. These include age, gender, personality, physical and mental state and being under the influence of alcohol, prescribed medicines, street drugs or over-the-counter medicines.^2,3 Studying the effects of any of these factors in isolation is extremely difficult. Some studies have attempted to categorize medicinal drugs according to how they affect driving performance.⁴ Some studies have assessed the effect of medication on tests such as response-time and attention,⁵ but these tests do not directly measure ability or inability to drive.

It has been estimated that up to 10% of people killed or injured in road traffic accidents (RTAs) are taking psychotropic medication.⁵ See Table 8.14. Patients with personality disorders and alcoholism have the highest rates of motoring offences and are more likely to be involved in accidents.⁵ People whose driving ability may be impaired through their illness or prescribed medication should inform their insurance company. Failure to do so is considered to be 'withholding a material fact' and may render the insurance policy void.

Effects of mental illness

Severe mental disorder is a prescribed disability for the purposes of the Road Traffic Act 1988.¹⁹ Regulations define mental disorder as including mental illness, arrested or incomplete development of the mind, psychopathic disorder or severe impairment of intelligence or social functioning. The licence restrictions that apply to each disorder can be found in Table 8.15. Note that licence restrictions may also apply to people with diabetes, particularly if treated with insulin or if there are established micro or macrovascular complications.

Many people with early dementia are capable of driving safely.²⁰ All drivers with new diagnoses of Alzheimer's disease and other dementias must notify the Drivers and Vehicle Licensing Agency (DVLA).^21,22 The doctor may need to make an immediate decision on safety to drive and ensure that the licensing agency is notified²³ There are no data to support ongoing driving assessments as a way of maintaining driving ability or improving road safety of drivers with dementia.²⁴

Effects of psychiatric medicines

The Road Traffic Act does not differentiate between illicit drugs and prescribed medicines. In the UK, a new liability offence came into effect in the summer of 2014 for drivers who are impaired after recreational use of drugs.²⁵ Therefore, any person who drives in a public place while unfit due to any drug, is liable to prosecution. The DVLA list of 'recreational drugs' includes some that can be prescribed such as morphine, amfetamines and benzodiazepines (the full list can be found on the MHRA website). A comprehensive report²⁶ describing the evidence behind the new laws and legal limits for driving is available.

Table 8.14 Psychotropic drugs and driving

Many psychotropics can impair alertness, concentration and driving performance. Medicines that block H₁, α₁-adrenergic or cholinergic receptors may be particularly problematic. Effects are particularly marked at the start of treatment and after increasing the dose. Drivers must be made aware of any potential for impairment and advised to evaluate their driving performance at these times. They must stop driving if adversely affected.²⁷ The use of alcohol will further increase any impairment. Many antipsychotics and antidepressants lower the seizure threshold. The DVLA advises this is taken into consideration when prescribing for a driver. Further information about the effects of psychotropics on driving can be found in Table 8.14.

Table 8.15 Summary of DVLA regulations for psychiatric disorders (November 2013)²⁰

Medication-induced sedation

Many psychotropics are sedating. The more sedating a medicine is, the more likely it is to impair driving ability. Other medicines, either prescribed or bought over the counter, may also be sedative and/or affect driving ability (e.g. antihistamines⁵). One study found that 89% of patients taking other psychotropics in addition to antidepressants failed a battery of 'fitness to drive' tests.²⁸ Since the degree of sedation any individual will experience is very difficult to predict, patients prescribed sedating medicines should be advised not to drive if they feel sedated.

DVLA: duty of the driver

It is the legal responsibility of the licence holder or applicant to notify the DVLA of any medical condition which may affect safe driving. A list of relevant medical conditions can be found in the DVLA'At a glance' guide.²⁰ Drivers must recognize signs of impaired driving performance due to medication or illness.

DVLA: duty of the prescriber

Make sure the patient understands that their condition may impair their ability to drive. If the patient is incapable of understanding, notify the DVLA immediately. Explain to the patient that they have a legal duty to inform the DVLA.

Note: the DVLA guidance specifies that patients under S17 of the Mental Health Act must be able to satisfy the standards of fitness for their respective conditions and be free from any effects of medication which would affect driving adversely, before resuming driving. Very few patients will fulfil these criteria.

General Medical Council guidelines for prescribers²⁹

• Patients who disagree with the diagnosis or the effect of the condition on their ability to drive should seek a second opinion and refrain from driving until this has been obtained.
• If the patient continues to drive while unfit, you should make every reasonable effect to persuade them to stop. This may include telling their next of kin if they agree you may do so.
• If they continue to drive, inform the DVLA. Tell the patient you are going to do this and write to the patient to confirm you have done so. Document the advice given clearly in the patient's notes.

References

1. Annas GJ. Doctors, drugs, and driving—tort liability for patient-caused accidents. N Engl J Med 2008; 359:521–525.
2. Metzner JL et al. Impairment in driving and psychiatric illness. J Neuropsychiatry Clin Neurosci 1993; 5:211–220.
3. Farkas RH et al. Zolpidem and driving impairment—identifying persons at risk. N Engl J Med 2013; 369:689–691.
4. Alvarez J, de Gier H, Mercier-Guyon C, Verstraete A. ICADTS Working Group: Catergorization system for medicinal drugs affecting driving performance. 2007. http://www.icadts.nl/medicinal.html
5. Noyes R, Jr. Motor vehicle accidents related to psychiatric impairment. Psychosomatics 1985; 26:569–580.
6. Biecheler MB et al. SAM survey on "drugs and fatal accidents": search of substances consumed and comparison between drivers involved under the influence of alcohol or cannabis. Traffic Inj Prev 2008; 9:11–21.
7. Oyefeso A et al. Fatal injuries while under the influence of psychoactive drugs: a cross-sectional exploratory study in England. BMC Public Health 2006; 6:148.
8. Brunnauer A et al. The effects of most commonly prescribed second generation antidepressants on driving ability: a systematic review: 70th Birthday Prof. Riederer. J Neural Transm 2013; 120:225–232.
9. Bramness JG et al. Minor increase in risk of road traffic accidents after prescriptions of antidepressants: a study of population registry data in Norway. J Clin Psychiatry 2008; 69:1099–1103.
10. Verster JC et al. Psychoactive medication and traffic safety. Int J Environ Res Public Health 2009; 6:1041–1054.
11. Grabe HJ et al. The influence of clozapine and typical neuroleptics on information processing of the central nervous system under clinical conditions in schizophrenic disorders: implications for fitness to drive. Neuropsychobiology 1999; 40:196–201.
12. Wylie KR et al. Effects of depot neuroleptics on driving performance in chronic schizophrenic patients. J Neurol Neurosurg Psychiatry 1993; 56:910–913.
13. Brunnauer A et al. The impact of antipsychotics on psychomotor performance with regards to car driving skills. J Clin Psychopharmacol 2004; 24:155–160.
14. Dassanayake T et al. Effects of benzodiazepines, antidepressants and opioids on driving: a systematic review and meta-analysis of epidemiological and experimental evidence. Drug Saf 2011; 34:125–156.
15. Verster JC et al. Hypnotics and driving safety: meta-analyses of randomized controlled trials applying the on-the-road driving test. Curr Drug Saf 2006; 1:63–71.
16. Etminan M et al. Use of lithium and the risk of injurious motor vehicle crash in elderly adults: case-control study nested within a cohort. BMJ 2004; 328:558–559.
17. Hashemian F et al. A comparison of the effects of reboxetine and placebo on reaction time in adults with Attention Deficit-Hyperactivity Disorder (ADHD). Daru 2011; 19:231–235.
18. Classen S et al. Evidence-based review on interventions and determinants of driving performance in teens with attention deficit hyperactivity disorder or autism spectrum disorder. Traffic Inj Prev 2013; 14:188–193.
19. The National Archives. Road Traffic Act 1991. 1991. http://www.legislation.gov.uk/ukpga/1991/40/contents
20. Driver and Vehicle Licensing Agency. At a glance guide to the current medical standards of fitness to drive. 2013. https://www.gov.uk/ government/publications/at-a-glance
21. DirectGov. Alzheimer's disease and driving. 2013. https://www.gov.uk/alzheimers-disease-and-driving
22. DirectGov. Dementia and driving. 2013. https://www.gov.uk/dementia-and-driving
23. Breen DA et al. Driving and dementia. BMJ 2007; 334:1365–1369.
24. Martin AJ et al. Driving assessment for maintaining mobility and safety in drivers with dementia. Cochrane Database Syst Rev 2013; 8: CD006222.
25. Medicines and Healthcare Products Regulatory Agency. New drug driving offence—implications for medicines packaging. London: MHRA; 2013. http://www.mhra.gov.uk/Howweregulate/Medicines/Medicinesregulatorynews/CON350699
26. Wolff K et al. UK Department of Transport - Driving under the Influence of Drugs. Report from the Expert Panel on Drug Driving. 2013. https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/167971/drug-driving-expert-panel-report.pdf
27. Department of Transport. Medication and Road Safety: A Scoping Study. Road Safety Research Report No. 116. 2010. http://www.dft.gov. uk/
28. Grabe HJ et al. The influence of polypharmacological antidepressive treatment on central nervous information processing of depressed patients: implications for fitness to drive. Neuropsychobiology 1998; 37:200–204.
29. General Medical Council. Good practice in prescribing and managing medicines and devices. 2013. http://www.gmc-uk.org/guidance/ethical_ guidance/14316.asp

Covert administration of medicines within food and drink

In mental health settings, it is common for patients to refuse medication. Some patients with cognitive disorders may lack capacity to make an informed choice about whether medication will be beneficial to them or not. In these cases, the clinical team may consider whether it would be in the patient's best interests to conceal medication in food or drink. This practice is known as covert administration of medicines. Guidance from the Nursing and Midwifery Council^1–3 and the Royal College of Psychiatrists⁴ exists in order to protect patients from the unlawful and inappropriate administration of medication in this way. The legal framework for such interventions would be either the Mental Capacity Act (MCA)⁵ or, more rarely, the Mental Health Act (MHA).⁶

Assessment of mental capacity^5,7

When it applies to the covert administration of medicines, the assessment of capacity regarding treatment is primarily a matter for doctors treating the patient.^5,7 Nurses will also have to be mindful of their own codes of professional practice and should be satisfied that the doctor's assessment is reasonable. In assessing capacity it is important to make the assessment in relation to the particular treatment proposed. Capacity can vary over time and the assessment should be made at the time of the proposed treatment. The assessment should be documented in the patient's notes and recorded in the care plan.

A patient is presumed to have the capacity to make treatment decisions unless he/she is unable to:

• understand the information relevant to the decision
• retain that information
• use or weigh that information as part of the process of making the decision, or
• communicate his/her decision (whether by talking, using sign language or any other means).

Guidance on covert administration

If a patient has the capacity to give a valid refusal to medication and is not detainable under the Mental Health Act, their refusal should be respected.

If a patient has the capacity to give a valid refusal and is either being treated under the Mental Health Act or is legally detainable under the Act, the provisions of the Mental Health Act with regard to treatment will apply, which are outside the scope of this chapter. In general, the Mental Health Act will only be used if the person is actively resisting admission and treatment. Someone who passively assents to admission and treatment can be admitted and treated without the Mental Health Act being used. If such a patient lacks capacity, the legal framework under which the patient is being treated is the Mental Capacity Act.

The administration of medicines to patients who lack the capacity to consent and who are unable to appreciate that they are taking medication (e.g. unconscious patients) should not need to be carried out covertly.

However, some patients who lack the capacity to consent would be aware, if they were not deceived into thinking otherwise.⁸ For example a patient with moderate dementia who has no insight and does not believe he needs to take medication, but will take liquid medication if this is mixed with his tea without him being aware of this. It is this group to whom the rest of this guidance will apply.

Treatment may be given to people who lack capacity if it has been concluded that that treatment is in the patient's best interests (Section 5, MCA⁵) and proportionate to the harm to be avoided (Chapter 6.41, MCA Code of Practice.⁸) So, there should be a clear expectation that the patient will benefit from covert administration, and that this will avoid significant harm (either mental or physical) to the patient or others. The treatment must be necessary to save the patient's life, to prevent deterioration in health or to ensure an improvement in physical or mental health.⁸

The decision to administer medication covertly should not be made by a single individual but should involve discussion with the multidisciplinary team caring for the patient and the patient's relatives or informal carers. It is good practice to hold a 'best interests meeting'⁹ (see below). Decisions should be carefully documented and each instance of covert administration recorded on the prescription chart.¹⁰ The decision should be subject to regular review,⁸ and the reviews also documented.

Summary of process

The process for covert administration of medicines should include the following safeguards.

• Assessment of capacity of the patient to make a decision regarding their treatment with medication. If the patient has capacity their wishes should be respected and covert medication not administered.
• A record of the examination of the patient's capacity must be made in the clinical notes, and evidence for incapacity documented.
• If the patient lacks capacity there should be a 'best interests meeting' which should be attended by relevant health professionals and a person who can communicate the views and interests of the patient (family member, friend or independent mental capacity advocate [IMCA]). If the patient has an attorney appointed under the Mental Capacity Act for health and welfare decisions, then this person should be present at the meeting.
• Those attending the meeting should ascertain whether the patient has made an Advanced Decision refusing a particular medication or treatment which can be used to guide decision-making.
• The 'best interests meeting' should consider whether a formal legal procedure such as the Mental Health Act or Deprivation of Liberty Safeguards (DoLs) is appropriate. Discussion of the indications and use of this legislation in the context of covert medication is outside the scope of this guidance, but specialist psychiatric and/or legal opinion should be sought in individual circumstances if necessary.
• Medication should not be administered covertly until a 'best interests meeting' has been held. If the situation is urgent it is acceptable for a less formal discussion to occur between carer/ nursing staff, prescriber and family/advocate in order to make an urgent decision, but a formal meeting should be arranged as soon as possible.
• After the meeting, there should be clear documentation of the outcome of the meeting. If the decision is to use covert administration of medication, a check should be made with the pharmacy to determine whether the properties of the medications are likely to be affected by crushing and/or being mixed with food or drink. The prescription card should be amended to describe how the medication is to be administered.
• When the medication is administered in foodstuff, it is the responsibility of the dispensing nurse to ensure that the medication is taken. This can be facilitated by direct observation or by nominating another member of the clinical team to observe the patient taking the medication.
• A plan to review on a regular basis the need for continued covert administration of medicines should be made.

References

1. Nursing and Midwifery Council. The Code: Standards of conduct, performance and ethics for nurses and midwives. London: NMC; 2008. http://www.nmc-uk.org/Publications/Standards/The-code/Introduction/
2. Nursing and Midwifery Council. Standards for medicines management. London: NMC; 2007. http://www.nmc-uk.org/Documents/NMCPublications/238747_NMC_Standards_for_medicines_management.pdf
3. Nursing and Midwifery Council. Covert administration of medicines. London: NMC; 2013. http://www.nmc-uk.org/Nurses-and-midwives/ Regulation-in-practice/Medicines-management-and-prescribing/Covert-administration-of-medicines/
4. Royal College of Psychiatrists. College Statement on Covert Administration of Medicines. Psychiatr Bull 2004; 28:385–386.
5. Office of Public Sector Information. Mental Capacity Act 2005, Chapter 9. 2005. http://www.opsi.gov.uk/
6. The National Archives. Mental Health Act 2007. 2007. http://www.legislation.gov.uk/ukpga/2007/12/contents
7. British Medical Association et al. Assessment of Mental Capacity, 3rd edn. London: The Law Society; 2009.
8. Department for Constitutional Affairs. Mental Capacity Act 2005 - Code of Practice. 2005. http://www.justice.gov.uk/.
9. Joyce T. Best interests: guidance on determining the best interests of adults who lack the capacity to make a decision (or decisions) for themselves. England and Wales. A report published by the Professional Practice Board of the British Psychological Society. 2007. http://www.bps. org.uk/
10. Treloar A et al. Concealing medication in patients' food. Lancet 2001; 357:62–64.

Further reading

Haw C et al. Covert administration of medication to older adults: a review of the literature and published studies. J Psychiatr Ment Health Nurs 2010; 17:761–768.

Haw C et al. Administration of medicines in food and drink: a study of older inpatients with severe mental illness. Int Psychogeriatr 2010; 22:409–416.

For Scotland

Mental Welfare Commission for Scotland. Good Practice Guide: Covert administration. 2013.

http://www.mwcscot.org.uk/media/140485/covert_medication_finalnov_13.pdf