Subsequent episodes Subsequent presentations may be due to relapse of psychotic symptoms af ter remission, a deterioration in or a change in the quality of partially treated psychotic symptoms, or a crisis relating to life events in a patient who, as a result of their illne ss, has an impaired ability to manage stress. Relapses can occur spontaneously in the absence of causative factors and in spite of good c ompliance with anti-psychotic treatment. However, very often relapses relate to medication non-compliance, drug or alcohol misuse or life stresses (or a combination of these). Often in an individual patient the time course, prodromal features and symptomatology of a relapse are characteristic \200\224the so-called \200\230relapse signature \200\231. Educa ting patient and carers about these warning signs, and awareness of and documentation of th ese features within the treating team, are important parts of relapse prevention. 1 Yung AR, Phillips LJ, McGorry PD, et al. (1998) Prediction of psychosis: a step towards i ndicated prevention of schizophrenia. Br J Psychiat Suppl 172: 14 \200\22320. 2 Miller TJ, McGlashan TH, Rosen JL, et al. (2002) Prospective diagnosis of the initial prodrome for sch izophrenia based on the Structured Interview for Prodromal Syndromes: preliminary evidence of interrater reliability and predictive validity. Am J Psychiat 159: 863 \200\2235. 06_Semple_Chap06.indd 189 12/7/2012 3:30:28 PM CHAPTER 6 Schizophrenia and related psychoses 190 Initial assessment of acute psychosis Issues affecting initial management decisions In view of the range and variety of presentations and the broad differential (b p. 180), it is dif \201 cult to be prescriptive in dealing with a patient who presents with psychotic sympto ms. Symptoms may range from mild para- noid ideas to elaborate and \201 rmly held delusio ns with associated auditory hallucinations urging the patient to violence. Often it is dif \201 cult to estab- lish a clear history initially, and assessment is focused on the immed iate concerns: \200 The risk they currently pose to themselves \200\224not just the possibility of acts of self -harm or suicide, but also because of other aspects of their behavior (e.g. police becoming involved, family relationships, work, continued driving, etc.). Risk of violence \200\224t he nature of risk ( with current symptoms (e.g. delusions about a speci \201 c person or g roup of individuals; what the \200\230voices \200\231 are telling them to do). The degree of insight retained by the patient and the likelihood of them cooperating with medical mana gement. Whether hospital admission or transfer to a psychiatric ward is warranted to assess and manage the acute symptoms (with or without the use of the Mental Health Act). Whether their current behavior is so disturbed as to require urgent treatment (b p. 990) to allow f urther assessment, including physical examination and other routine investigations (b p. 18 7). The person \200\231s current social circumstances and the level of support available to them (partner, relatives, friends, community psychiatric nurse [CPN], etc.) that may allow some \202 exibility in management (as well as being a source of third-party information) . b p. 692) and any association The greatest in \202 uence on your course of action will often be the reason why the perso n has been referred in the \201 rst place (e.g. brought up by a concerned relative, no lo nger able to be managed at home, breach of the peace, self-referral because of own concerns , attempted suicide). When there is a good account of the history of the presenting complaint(s), it may be possi ble to establish the most likely diagnosis and proceed accordingly, e.g. a drug- or alcohol -related disorder, acute confu- sional state (b p. 790), \201 rst episode of schizophreni a (b p. 188), relapse of known schizophrenia (b p. 189), delusional disorder (b p. 220), ac ute psychotic disorder (b p. 226). During initial assessment, particularly with unmedicated patients, record (verbatim if poss ible) speci \201 c aspects of the patient \200\231s psychopathology (nature and content of delusions and hallucinations), before they become modi \201 ed by the necessary use of me dication. This information is important as it will in \202 uence later decisions regarding , for example, assessment of treatment response and need for continued use of the Mental He alth Act (MHA). Many patients with a psychotic presentation will have comorbid drug and/or alcohol problems . The fact that the psychotic episode is suspected to be wholly or partially attributable t o comorbid substance use should 06_Semple_Chap06.indd 190 12/7/2012 3:30:28 PM INITIAL ASSESSMENT OF ACUTE PSYCHOSIS 191 not be allowed to affect the treatment offered acutely, which should be planned on the basi s of the nature and severity of the psychotic symptoms and the associated risk. On recovery from the acute episode the comorbid substance use should become a focus for clinical atten tion. The need for hospital admission As noted in Issues affecting initial management decidions, b p. 190, cer- tain clinical features and situations will determine whether hospital admis- sion (or transfer to psychiatric ward) is necessary: \200 \200 High risk of suicide or homicide. Other illness-related behavior that endangers relationshi ps, reputation, or assets. Severe psychotic, depressive, or catatonic symptoms. Lack of cap acity to cooperate with treatment. Lack or loss of appropriate psychosocial supports. Failu re of outpatient treatment. Non-compliance with treatment plan (e.g. depot medication) for patients detained under the MHA. Signi \201 cant changes in medication for patient at high risk of relapse (including clozapine \200\230red \200\231 result \200\224b p. 213). Need to address comorbid conditions (e.g. inpatient detoxication, physical problems, serious med ication side-effects). \200 \200 \200 \200 Suitability of the ward environment A busy psychiatric ward may not be an ideal environment for a patient experiencing acute psychotic symptoms. As far as possible the person should be nursed in calm surroundings (a single room, if possible), with minimal stimulation (e.g. unfamiliar people, TV, radio). A balance should be struck between the need for regular obs ervation and the likelihood that this may reinforce persecutory delusions. If behavior beco mes unmanageable, despite regular medication, it may be necessary to consider referral of t he patient to a more secure environment, e.g. an intensive psychiatric care unit (IPCU). Early review Regular review is critical in the \201 rst 72hrs to assess any improvement i n mental state, response to medication, level of observation needed, and carry out statutor y duties under the MHA (including the need for contin- ued detention, if emergency powers h ave been used). This is also a time for information-gathering from friends, family, GP, oth er agencies, etc. and organizing any investigations, including physical examination and rou tine blood tests that may not have been possible initially. 06_Semple_Chap06.indd 191 12/7/2012 3:30:28 PM CHAPTER 6 Schizophrenia and related psychoses 192 Initial treatment of acute psychosis The management of psychotic patients should include, w herever possible, the usual features of good medical practice: undertaking a comprehensive assessment of medical, social, and psychological needs; involving patients and their relati ves in decisions about medical care; and providing patients and carers with clear verbal an d, if necessary, written information (see NICE guidelines, Box 6.1). Emergency treatment of behavioral disturbance Follow guidance as detailed for the managemen t of acute behavioral dis- turbance (b p. 990). Points to note \200 Attempts to defuse the situation should be attempted, whenever possible. Reassurance and th e offer of voluntary oral/intramuscular medication is often successful. The content of delu sions and hallucinations is of poor diagnostic value, but may better predict violence/behav ioral disturbance. Act decisively and with suf \201 cient support to ensure restraint and forcible administration of medication proceeds without unnecessary delay or undue risk to t he patient or staff. Do not attempt to manage severe violence on an open ward when secure f acilities with appropriately trained staff are available elsewhere. Instigation of antipsychotic treatment In the treatment of psychotic symptoms, antipsychoti c medication has the strongest evidence base. Although little evidence exists to support th e choice of one drug over the other, the following may be used as a guide to treatment. Option 1 \200 Commence an SGA (e.g. olanzapine, amisulpride, risperidone, quetiapine \200\224see p. 202) at an effective dose (see the British National Formulary [BNF]). Use long-acting BDZ (e.g. diazepam) to control non-acute anxiety/ behavioral disturbance. Option 2 \200 Prescribe a low potency FGA (such as chlorpromazine, initially in the range 75 \200\223200m g/day in divided doses) for a \201 rst episode. Increase the dose according to clinical e ffect and the need for sedation. Previous episodes and the response/side-effects experience d should inform the management of subsequent episodes. No additional antipsychotic bene \201 t is likely when doses of 400 \200\223600mg chlorpromazine (or equivalent) are exceede d; however, sedation may be a useful effect of increasing the dose above this level. \200 06_Semple_Chap06.indd 192 12/7/2012 3:30:28 PM INITIAL TREATMENT OF ACUTE PSYCHOSIS 193 Extra-pyramidal side-effects (EPSEs) Extra-pyramidal side-effects including dystonias, Park insonism and akathisia are common side-effects of treatment with antipsychotic medication, and are a frequent cause of non-compliance. \200 EPSEs are less likely with option 1, although the tolerability of both options overall is a pproximately equal. Prescribe procyclidine (or alternative) orally as required for Parkinso nian side-effects. Review regularly, since requirement for procyclidine may diminish over t ime and the drug may contribute to non-response and tardive dyskinesia. Box 6.1 Updated NICE guidelines (CG821) advice on second generation antipsychotics (SGAs) Although previous guidelines (2002) had advocated use of \200\230atypical \200\231 drugs a s \201 rst line choice, this is no longer the case. Instead, for people with newly diagno sed schizophrenia, NICE advises: \200 \200 Offering oral antipsychotic medication. Providing information and discuss the bene \201 ts and side-effect pro \201 le of each drug with the service user. The choice of drug should be made by the service user and health care professional together, considering: the relati ve potential of individual antipsychotic drugs to cause extra-pyramidal side-effects (inclu ding akathisia), metabolic side-effects (including weight gain) and other side-effects (inc luding unpleasant subjective experiences); the views of the carer where the service user ag rees. Not initiating regular combined antipsychotic medication, except for short periods (e .g. when changing medication). Offering clozapine to people with schizophrenia whose illnes s has not responded adequately to treatment despite the sequential use of adequate doses of at least two different antipsychotic drugs, at least one of which should be a non-clozapin e second generation antipsychotic. 1 NICE clinical guideline 82 (Mar 2009) Schizophrenia: core interventions in the treatment and management of schizophrenia in adults in primary and secondary care. http://www.nice.or g.uk/ nicemedia/live/11786/43608/43608.pdf 06_Semple_Chap06.indd 193 12/7/2012 3:30:28 PM CHAPTER 6 Schizophrenia and related psychoses 194 Maintenance phase The post-acute phase With the emergence of \200\230stability \200\231 (i .e. less active psychotic symptoms, less behavioral disturbance), treatment shifts towards the gradual simpli \201 ca- tion of medication regimes and maximization of tolerability. T he patient may be more able to engage actively with other therapeutic modalities available in the hospital environment. Time to remission of symptoms is very variable and may take 3 \200\2239mths or more. It is important the patient and their family/friends have realistic expectations. Continuing treatment A more considered view of management may be taken once maximal improve ments are considered to have occurred. This is the time to estab- lish the minimal effectiv e dose of medication and maintenance regimes can often be signi \201 cantly lower than tho se needed for management of the acute phase of the illness. A secondary goal is the minimiz ation of side- effects with the aim of establishing compliance with medication. Finally, th ere is the more complex goal of rehabilitation: returning the patient to their highest poss ible level of social and occupational functioning. The \201 nal steps in this process may require the input, where available, of better resourced multidisciplinary rehabilitation u nits or community teams over many months with the ultimate aims of successful discharge (b p. 196) and outpatient follow-up (b p. 198). Comorbid depression Depression can affect up to 70% of patients in the acute phase but tend s to remit along with the psychosis. In the maintenance phase, post- psychotic or post-schi zophrenic depression occurs in up to 1/3 of patients and there is some evidence that TCAs ( e.g. imipramine) may be effective. Surprisingly, despite it being common clinical practice, there are few studies supporting other interventions such as SSRIs. Managing negative symptoms Speci \201 c interventions may help to mitigate the impact of p ersistent nega- tive symptoms: \200 Ensure EPSEs (esp. bradykinesia) are detected and treated by anticholinergics, amantadine, reducing antipsychotics, or switching to lower potency/SGA agent. If there is evidence of d ysphoric mood consider treating with antidepressants, anxiolytics, reducing antipsychotic d ose, supportive management, or switching to SGA. Address the contribution of the environmen t (e.g. institutionalization, lack of stimulation) by resocialization and/or rehabilitation . If patient is on long-term medication consider reduction to minimal reasonable maintenanc e dose, switching to SGA, or clozapine. If clozapine is prescribed, consider augmentation w ith antidepressant, lamotrigine, or a suitable second antipsychotic (see b p. 208). 06_Semple_Chap06.indd 194 12/7/2012 3:30:29 PM MAINTENANCE PHASE 195 Addressing comorbid substance use As previously noted there is signi \201 cant comorbidity of substance abuse in patients with schizophrenia. Whilst this may complicate and exacerba te positive and negative symptoms, sometimes patients believe they are self- medicating and may be reluctant to give up a \200\230useful \200\231 treatment. Elements of a pragmatic approach include: \200 A comprehensive assessment, including why and how substances are taken, as well as routine testing for substance misuse. Optimization of antipsychotic medication and consideration of clozapine for patients with persisting substance misuse. The offer of speci \201 c treatm ent for substance misuse and possibly referral to local drug and alcohol services \200\224w hilst psychosocial approaches will be the mainstay (including relapse prevention), the poss ible bene \201 ts of pharmacotherapy should not be ignored e.g. nicotine substitution/with drawal, alcohol detoxi \201 cation, opiate substitution. Box 6.2 A note on prodromal interventions Before an individual ful \201 ls DSM-IV/ICD-10 criteria for schizophrenia, there may be an intervening period of disturbed behavior and partial psychotic symptoms that suggest, espe cially in the presence of other risk factors, that schizophrenia is imminent and inevitable (see p. 188). This observation has led some to propose early interventions for schizo- phr enia which aim to prevent a schizophrenic episode by treating these prodromal symptoms. Pre liminary evidence suggests that low-dose antip- sychotics, CBT, and antidepressants can imp rove presenting symptoms1. However, there is no convincing evidence yet that any interventi on can delay, prevent, or reduce the severity of the onset of a psychotic illness. Neither is there evidence that the mean duration of untreated psycho- sis (DUP) in patients who dev elop psychosis improves the long-term outcome. Recent guidance (e.g. BAP Schizophrenia Cons ensus Group) recommends2: \200 Develop a therapeutic relationship to allow for further assessment, review, \200\230watchf ul waiting \200\231, and monitoring of symptoms. Assess the nature and impact of any substa nce use. Any use of antipsychotic medication should be treated as an off- label, short-term , individual trial using the lowest possible dose and with careful monitoring of symptom re sponse and side-effects. Individual CBT is an acceptable alternative to drug treatment. \200 The resource implications necessitate a speci \201 c early intervention serv- ice which ma y not be economically justi \201 ed. 1 Ruhrmann S, Bechdolf A, K hn K-U, et al. (2007) Acute effects of treatment for prodromal symptoms for people putatively in a late initial prodromal state of psychosis. Br J Psychi at 191 (Suppl. 51): 88 \200\22395. 2 www.bap.org.uk/pdfs/Schizophrenia_Consensus_Guideline_ Document.pdf 06_Semple_Chap06.indd 195 12/7/2012 3:30:29 PM CHAPTER 6 Schizophrenia and related psychoses 196 Discharge planning Good communication between members of the multidisciplinary team (psychi atry, community nurse, GP, social worker, etc.) is essential for good overall care. This ma y be formalized using the care program approach (CPA), when patients are detained under the MHA, although many of the components are useful in everyday practice: Components of CPA (as implemented in Edinburgh): \200 \200 \200 Assess clinical and other needs. Formulate a care plan. Arrange discharge planning meeting where patient, carer(s), and key clinical staff are invited. Appoint a care manager who sho uld be contacted in case of concern. Maintain contact with the patient. Decide on criteria for recall and/or other interventions. Document the people involved in the care package and their responsibilities. Arrange to meet again as a group. \200 \200 \200 Medication Continue antipsychotic medication at minimum necessary dose. Possible regimes in clude: \200 An SGA antipsychotic (e.g. amisulpride, olanzapine, risperidone, quetiapine). A preferably non-sedating, FGA antipsychotic (e.g. tri \202 uoperazine, \202 upentixol, haloperidol). Depot antipsychotic medication, particularly where use of oral medication has resulted in relapse due to non-compliance. Depot medication is slightly more effective1 than oral antip sychotic treatment. High-potency FGA antipsychotics (tri \202 uoperazine, haloperidol) and olanzapine may be given once daily. This may be an advantage in non- compliant, institutio nalized, or cognitively impaired patients. In patients with complicated drug regimes, cogni tive impairment, or dubious compliance, consider a compliance aid such as a multicompartmen t compliance aid (e.g. Dosette box). Psychological2 \200 \200 \200 Family therapy and psychoeducation are effective in reducing relapse. Less convincing evide nce also exists for CBT. Compliance therapy may be helpful. Social/community \200 \200 Social work and housing involvement are often necessary. Community psychiatric nurses (CPNs ) may help to provide information/education and monitor for early signs of relapse. For pat ients on depot, non-attendance at GP surgery/CPN appointment may act as an early warning sy stem. 06_Semple_Chap06.indd 196 12/7/2012 3:30:29 PM DISCHARGE PLANNING 197 Service provision \200 \200 \200 \200 Community mental health teams provide effective treatment. Assertive community treatment ma y provide additional bene \201 ts. CPA may reduce the risk of losing contact. Day hospital s can provide an alternative to inpatient care in some situations. 1 Adams CE, Fenton MK, Quraishi S, and David AS (2001) Systematic meta-review of depot anti psychotic drugs for people with schizophrenia. Br J Psychiat 179: 290 \200\2239. 2 Nadeem Z , McIntosh A and Lawrie S (2003) Schizophrenia. Clin Evidence 9: 1103 \200\22333. 06_Semple_Chap06.indd 197 12/7/2012 3:30:29 PM CHAPTER 6 Schizophrenia and related psychoses 198 Outpatient treatment and follow-up Medical \200 \200 \200 \200 \200 Conduct a MSE at every appointment. Enquire about side-effects and attitude to medication. Record any recent life events or current stresses. Enquire about suicidal ideas and, if app ropriate, homicidal ideas. When symptoms appear unresponsive to treatment, review the histo ry and provide additional investigations/interventions as appropriate (e.g. clozapine). Con duct appropriate investigations where complications of illness or its treatment arise (e.g. LFTs, FBC, U&Es, glucose), or where monitoring is indicated (e.g. high-dose guidelines b p . 209, ECG \200\224 when cardiac complications are common). Psychological \200 Above all, try to provide supportive and collaborative treatment wherever possible. Provide education about schizophrenia and its treatment. Do not dismiss concerns, even if apparent ly based on delusional content.1 Offer to meet family members or carers where appropriate. Be aware that following an acute episode, post-psychotic depression (see b p. 194) is parti cularly common but also treatable.2 \200 \200 Social \200 \200 Remember statutory obligations (e.g. review of compulsory powers). Consider referral to soc ial work where there are housing, bene \201 t, or other problems. Drop-in community center s and other support provided by non- statutory or voluntary organizations are often helpful . Consider interventions offered by other professions (e.g. occupational therapy, physiothe rapy) when particular problems arise (e.g. poor sleep, hygiene, anxiety management, etc.). Some patients and their carers \201 nd user organizations helpful (e.g. SANE or Rethink \200\224see useful addresses b p. 1017). There is usually a large degree of uncertainty regarding the course and prognosis in \201 rst-episode patients, regardless of their presenting symp- toms or demographic/personal hi story. 06_Semple_Chap06.indd 198 12/7/2012 3:30:29 PM OUTPATIENT TREATMENT AND FOLLOW-UP 199 Box 6.3 Outcome in schizophrenia Approximate guide to course and prognosis at 13yrs \200\231 follow-up:1 \200 \200 \200 \200 \200 Approximately 15 \200\22320% of \201 rst episodes will not recur. Few people will remain in employment. 52% are without psychotic symptoms in the last 2yrs. 52% are without negativ e symptoms. 55% show good/fair social functioning Prognostic factors Poor prognostic factors \200 \200 \200 \200 \200 \200 poor premorbid adjustment insidious onset onset in childhood or adolescence cognitive impai rment enlarged ventricles symptoms ful \201 l more restrictive criteria (e.g. DSM-IV) Good prognostic factors \200 marked mood disturbance, especially elation, during initial presentation family history of affective disorder female sex living in a developing country \200 \200 1 Mason P, Harrison G, Glazebrook C, et al. (1995) Characteristics of outcome in schizophre nia at 13 years. BJP, 167: 596 \200\223603. 1 McCabe R, Heath C, Burns T, and Priebe S (2002) Engagement of patients with psychosis in the consultation: conversation analytic study. BMJ 325: 1148 \200\22351. 2 Whitehead C, Mos s S, Cardno A, and Lewis G (2003) Antidepressants for the treatment of depression in people with schizophrenia: a systematic review. Psychol Med 33: 589 \200\22399. 06_Semple_Chap06.indd 199 12/7/2012 3:30:29 PM CHAPTER 6 Schizophrenia and related psychoses 200 First generation antipsychotics (FGAs) Group 1 \200\224aliphatic phenothiazines Chlorpromaz ine-like drugs with mainly anti-adrenergic and antihistamin- ergic side-effects including p ronounced sedation, moderate antimuscarinic effects and moderate EPSEs (for drug doses equi valent to 100mg chlorpro- mazine \200\224see Table 6.3). Chlorpromazine (non-proprietary an d Largactil ) \200 \200 \200 75 \200\223300mg daily in divided doses (or at night) \200\224max 1g daily Available as I/M injection (25 \200\22350mg every 6 \200\2238hrs) Also available as 25mg or 100mg supposito ries Promazine \200 \200 \200 400 \200\223800mg daily in divided doses Rarely causes haemolytic anemia Usually used for a gitation and restlessness, e.g. 100mg qds (25 \200\22350mg for elderly) Group 2 \200\224piperidine phenothiazines Thioridazine-like drugs with mainly antimuscarini c side-effects and fewer EPSEs than groups 1 and 3 Pericyazine (Neulactil ) \200 \200 75 \200\223300mg daily in divided doses In behavioral management: 15 \200\22330mg daily in divided doses Group 3 \200\224piperazine phenothiazines and others Tri \202 uoperazine-like drugs with m ainly anti-dopaminergic side-effects. These drugs are potent antipsychotics but tend to pro duce troublesome EPSEs, particularly at higher doses. They have limited sedative properties . Tri \202 uoperazine (non-proprietary and Stelazine ) \200 \200 No stated maximum dose For psychosis or behavioral management \200\2245mg bd increased by 5 mg after 1wk then every 3 days according to response Fluphenazine (Prolixin) \200 Available in decanoate (long-acting) form Perphenazine (Fentazin ) \200 \200 \200 12 \200\22324mg daily For behavioral management usually 4mg tds Rarely causes SLE Flupentixol (Depixol ) \200 \200 3 \200\2239mg twice daily (max 18mg daily) Also available as depot (see b p. 216) Zuclopenthixol (Clopixol ) \200 \200 20 \200\22330mg daily in divided doses, max 150mg daily acetate \200\224for management of a cute Available in injectable forms as behavioral disturbance (Clopixol acuphase ) and deca noate \200\224for depot injection (Clopixol Conc ) \200\224see b p. 216 06_Semple_Chap06.indd 200 12/7/2012 3:30:29 PM FIRST GENERATION ANTIPSYCHOTICS 201 Haloperidol (non-proprietary and Haldol ) \200 \200 1.5 \200\2235mg 2 \200\2233 times daily in divided doses (max 30mg daily) Available as IM i njection (2 \200\22310mg every 4 \200\2238 hrs, max 18mg daily) Pimozide (Orap ) \200 2 \200\22320mg daily \200 Increase slowly by 2 \200\2234mg at in tervals not less than 1wk \200 May be more effective for monodelusional states, e.g. hypo chondriasis, delusional jealousy Sulpiride (non-proprietary and Dolmatil ) \200 \200 200 \200\223400mg twice daily Lower max dose for negative symptoms (800mg daily) than for p ositive symptoms (2.4g daily) Table 6.3 Antipsychotic dose equivalents Drug Equivalent dose ORAL 1st generation Benperidol Chlorpromazine Flupentixol Haloperidol Pericyazine Perphenaz ine Pimozide Promazine Sulpiride Tri \202 uoperazine Zuclopenthixol 2 nd generation Amisul pride Aripiprazole* Clozapine Olanzapine Paliperidone* Quetiapine* Risperidone DEPOT Flupen tixol decanoate Fluphenazine decanoate Haloperiol decanoate Olanzapine pamoate* Paliperidon e* Pipothiazine palmitate Risperidone depot Zuclopenthixol decanoate 2mg 100mg 2mg 3mg 24mg 8mg 2mg 100mg 200mg 5mg 25mg 100mg 10mg 100mg 5mg 0.75 \200\2231.5mg 50 \200\22375mg 0.5 \200\2231mg 10mg/wk 5 \200\22310mg/wk 15mg/wk 37.5mg/wk 7.5mg/wk 10mg/wk 12.5mg/wk 100mg/wk based on ef \201 cacy data 06_Semple_Chap06.indd 201 12/7/2012 3:30:29 PM CHAPTER 6 Schizophrenia and related psychoses 202 Second generation antipsychotics (SGAs1) Although not a separate class of antipsychotics, t he newer \200\230atypical \200\231 drugs do have a slightly different pharmacokinetic pro \201 le. They have a wider therapeutic range and are generally less likely to cause EPSEs and raise serum prolactin levels (for completeness, additional SGAs are listed in Box 6.4). Olanzapine (Zyprexa ) \200 \200 \200 2A = H1 = M1 > 5-HT2C > D2 > Receptor antagonism: 5-HT Optimum dose 5 \200\22320mg per day. Available as an orodispersib le tablet, a short-acting intramuscular (IM) injection and depot (olanzapine embonate/olanz apine pamoate or ZypAdhera see b p. 217). EPSEs similar to placebo in clinical doses with less increase in prolactin than haloperidol or risperidone. Side-effects of sedation, weig ht gain, dizziness, dry mouth, constipation, and possible glucose dysregulation. 1 > D1. Risperidone (Risperdal ) \200 2 > D2 = 1 = 2; little histamine H1 af \201 nity; Receptor antagonism: 5-HT minimal D1, 5-HT1 af \201 nity. Available as orodispersible tabl et and depot preparation (Risperdal Consta see b p. 217). Dosage 4 \200\2236mg daily give n in 1 \200\2232 doses (max 16mg daily). Less EPSEs than conventional antipsychotics at low er doses, but dystonias and akathisia can occur (esp. if dose >6mg or in elderly) and can r aise prolaction (PL) and cause weight gain. \200 Paliperidone (Invega ) \200 Paliperidone (9-OH risperidone) is the major active metabolite of risperidone. Receptor ant agonism: as for risperidone. Available as modi \201 ed release tablet or depot preparation (Xeplion see b p. 217). Dosage 6mg in the morning, adjusted in increments of 3mg over at l east 5 days; usual range 3 \200\22312mg daily. Low potential for EPSEs and, due to limited hepatic metabolism, reduced drug interactions. \200 Quetiapine (Seroquel ) \200 \200 \200 \200 1 > 1 > 5-HT2> 2 > D2. Receptor antagonism: H Usual dose 300 \200\223450mg daily in two divided doses (max 750mg d aily). EPSEs = placebo with no increase in prolactin. Can cause sedation, dizziness (postur al hypotension), constipation, dry mouth, weight gain, and alterations in triglycerides and cholesterol. 06_Semple_Chap06.indd 202 12/7/2012 3:30:29 PM SECOND GENERATION ANTIPSYCHOTICS 203 Clozapine (Clozaril , Denzapine , Zaponex ) See b pp. 210 \200\22315. Amisulpride (non-p roprietary and Solian ) \200 Selective and equipotent antagonism for D af \201 nity for other receptors. Similar ef \201 cacy to haloperidol for acute and chronic schizophrenia. Optimum dose 400 \200\223800 mg (max 1.2g) per day in two divided doses. Lower dose (50 \200\223300 mg) may be more effe ctive for patients with mainly negative symptoms. EPSEs similar to placebo at lower doses b ut dose-dependent EPSEs and prolactinaemia at higher doses. Less weight gain compared with risperidone or olanzapine. 2 and D3 with negligible \200 \200 Aripiprazole (Abilify ) D \200 2 receptor partial agonist; partial agonist at 5-HT1A receptors; high-af \201 nity antagon ist at 5-HT2A receptors; low/moderate af \201 nity antagonist at H1 and Dosage 10 \200 \22330mg once daily, optimum dose 10 \200\22320mg once daily. Low EPSEs similar to placebo at all doses (akathisia-like symptoms can occur in the \201 rst 2 \200\2233wks of treatme nt with associated insomnia \200\224use of additional hypnotic may be clinically necessary) . Does not increase plasma prolactin levels (and may decrease levels) and weight gain is le ss likely. 1 receptors; no anticholinergic effect. \200 1 In deference to the BNF and in light of recent controversies over classi \201 cation of antipsychotics, we have adopted the abbreviations & FGA and SGA for consistency only. It ma y in fact be better to simply call them all \200\230antipsychotics \200\231. For further d iscussion see Kendall T (2011) The rise and fall of the atypical antipsychotics Br J Psychi at 199: 266 \200\2238. 06_Semple_Chap06.indd 203 12/7/2012 3:30:29 PM CHAPTER 6 Schizophrenia and related psychoses 204 Box 6.4 Other SGAs (not currently listed in BNF) Zotepine (Zoleptil ) Discontinued by Healthcare Logistics from the UK market from Jan 2011 for commercial reason s. \200 High af \201 nity for D receptors, 25 \200\223100mg tds Inhibits NE re-uptake Ef fective against positive and negative symptoms of schizophrenia but controlled trial data l imited EPSEs less than FGAs Increased risk of seizures at higher doses (above 300mg) Weight gain, sedation, constipation, asthenia, dry mouth, akathisia Raised hepatic enzymes 1 and D2 receptors, also 5-HT2, 5-HT6, and 5-HT7 \200 \200 \200 \200 Sertindole (Serdolect ) Voluntarily withdrawn by Lundbeck in Dec 1998 due to concerns abou t arrhythmias associated with increase in QTc. Limited reintroduction in Jun 2002 in Europe under strict monitoring for patients in clinical trials and who are intolerant of at least one other antipsychotic. D \200 \200 \200 \200 \200 \200 2, 5-HT2, and 1 antagonist with D2 limbic selectivity Effective against positive and negative symptoms of schizophrenia 12 \200\22320mg single da ily dose (max 24mg daily) EPSEs = placebo Increase in QTc \200\224needs ECG monitoring Othe r side-effects include: nasal congestion, decreased ejaculatory volume, postural hypotensio n and dry mouth and raised liver enzymes Approximate guide to course and prognosis at 13 years \200\231 follow-up:1 \200 \200 \200 \200 \200 Approximately 15 \200\22320% of \201 rst episodes will not recur. Few people will remain in employment. 52% are without psychotic symptoms in the last two years. 52% are without ne gative symptoms. 55% show good/fair social functioning Prognostic factors Poor prognostic factors \200 \200 \200 \200 \200 \200 poor premorbid adjustment insidious onset onset in childhood or adolescence cognitive impai rment enlarged ventricles symptoms ful \201 ll more restrictive criteria (e.g. DSM-IV) Good prognostic factors \200 marked mood disturbance, especially elation, during initial presentation family history of affective disorder female sex living in a developing country \200 \200 06_Semple_Chap06.indd 204 12/7/2012 3:30:29 PM This page intentionally left blank CHAPTER 6 Schizophrenia and related psychoses 206 Antipsychotic side-effects Tolerability No single antipsychotic is substantially better tol erated than another at daily doses of <12mg haloperidol or equivalent. However, FGAs pre- s cribed above this range are less well tolerated and probably also less effective than SGA d rugs (Box 6.5). The choice of antipsychotic therefore depends substantially on the pro \201 le of side-effects and which ones are more important to avoid. \200 Sedation Avoid chlorpromazine/promazine. Prescribe high-potency antipsychotics (e.g. halope ridol) or non-sedating SGA (risperidone, amisulpride). Weight gain haloperidol, \202 uphe nazine. EPSEs Postural hypotension amisulpride, tri \202 uoperazine. Avoid phenothiazines, olanzapine and clozapine. Prescribe \200 Avoid high-dose FGAs. Prescribe SGA. Avoid phenothiazines. Prescribe haloperidol, Extra-pyramidal side-effects (EPSEs) \200 Acute dystonia sternocleidomastoid and tongue, although can be widespread (e.g. opisthoclon us); eye muscle involvement (e.g. oculogyric crisis) may occur. Virtually always distressin g and preceded by increasing agitation. Treatment Parenteral antimuscarinic (e.g. procyclid ine 10mg intravenously [IV]) \200\224see b p. 954 for more detail. Parkinsonism after admin istration. Treatment Consider dose reduction/use of oral antimuscarinic (e.g. procyclidine 5mg three times daily [tds]) \200\224 see b p. 944 for more detail. Akathisia Occurs usuall y >1mth after initiation of antipsychotic drug. Treatment Propranolol and benzodiazepines m ay be helpful. Symptoms can be notoriously dif \201 cult to treat \200\224see b p. 946 for more detail. Tardive dyskinesia (TD) (i.e. athetosis) and sudden involuntary movements, ty pically of the oral \200\223lingual region (chorea). Symptoms of TD tend to be irreversible . Treatment1 Although a consequence of antipsychotic treatment, there is little evidence th at a reduction in the dose of antipsychotic improves symptoms in the short or long term. Vi tamin E may prevent deterioration but does not improve established symptoms \200\224see b p . 950. Contraction of muscle group to maximal limit, typically Tremor, rigidity, and bradykinesia occurring >1wk Restlessness, usually of lower limbs, and a drive to move. Continuous slow writhing movements Anticholinergic side-effects Dry mouth, blurred vision, dif \201 culty passing urine, urin ary retention, con- stipation, rarely: ileus, glaucoma. Anti-adrenergic side-effects Postural hypotension, tachycardia (sometimes bradycardia), sex ual dys- function (particularly erectile dysfunction \200\224see b p. 938). 06_Semple_Chap06.indd 206 12/7/2012 3:30:30 PM ANTIPSYCHOTIC SIDE-EFFECTS 207 Antihistaminic side-effects Sedation, weight gain (although precise mechanism unclear \200 \224see b p. 930). Idiosyncratic Cholestatic jaundice, altered glucose tolerance, hypersensitivity reac- tions , skin photosensitivity (sun block important in sunny weather), yellow pigmentation to skin (chlorpromazine), neuroleptic malignant syndrome (rigidity, \202 uctuating consciousness , and pyrexia) \200\224may be fatal, requires immediate transfer to general medical care an d usually ICU/anesthetic support/dantrolene may be helpful \200\224see b p. 956 for more de tail. Box 6.5 SGAs vs. FGAs? Recent effectiveness studies such as the Clinical Antipsychotic Trials of Intervention Effe ctiveness (CATIE),1 the Cost Utility of the Latest Antipsychotic drugs in Schizophrenia Stu dy (CUtLASS),2 and the European First-Episode Schizophrenia Trial (EUFEST)3 have been inter - preted as showing no differences between FGAs and SGAs (with the possible exception of cl ozapine and perhaps olanzapine). Although this may be true in terms of overall effectivenes s, most clinicians (and patients) would agree there are many real differences among drugs, particularly when it comes to side-effects. Whilst guidelines from NICE or the BAP may prov ide helpful frameworks for rational prescribing, treatment ought to be individualized throu gh a shared decision-making process. Tolerability is a huge factor in adherence (see b p. 9 24) and it ought to be remembered that the best antipsychotic in the world will not work if the patient does not actually take it. 1 Lieberman JA, Stroup TS, McEvoy JP, et al. (2005) Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. NEJM 353: 1209 \200\2231223. 2 Jones PB, Barnes TRE, Davies L, et al. (2006) Randomized controlled trial of the effect on quality of life of sec ond- vs. \201 rst-generation antipsychotic drugs in schizophrenia: Cost Utility of the La test Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1). Arch Gen Psychiatry 63: 1079 \200\22387. 3 Kahn RS, Fleischhacker WW, Boter H, et al. (2008) Effectiveness of antipsycho tic drugs in \201 rst-episode schizophrenia and schizophreniform disorder: an open random ized clinical trial. Lancet 371: 1085 \200\22397. 1 Soares-Weiser KV and Joy C (2003) Miscellaneous treatments for neuroleptic-induced tardiv e dyskinesia. Cochrane Database Syst Rev 3: CD000208. 06_Semple_Chap06.indd 207 12/7/2012 3:30:30 PM CHAPTER 6 Schizophrenia and related psychoses 208 An approach to treatment-resistant schizophrenia (TRS) De \201 nition Treatment resistance is the failure to respond to two or more antipsy- chotic medications given in therapeutic doses for 6wks or more. Patients with refractory symptoms generally have more severe functi onal impair- ments and are more likely to have abnormalities of cerebral structure and neur opsychology. See Box 6.6 for guidelines.