Muddling A feature of schizophrenic thought disorder caused by simul- taneous derailment an d fusion. The speech so produced may be very bizarre. Multiple personality The \201 nding of two or more distinct \200\230personali- ties \200 \231 in one individual. These personalities may answer to different names, exhibit markedly different behaviors, and describe amnesia for periods when other personalities were active . This symptom is most probably an iatrogenic condition produced during exploratory psychot herapy in sug- gestible individuals. Mutism Absence of speech without impairment of consciousness. Negative symptoms (of schizophrenia) The symptoms of schizo- phrenia which re \202 ect imp airment of normal function. They are: lack of volition, lack of drive, apathy, anhedonia, \202 attening of affect, blunting of affect, and alogia. Believed to be related to cortica l cell loss. Negativism A motor symptom of schizophrenia where the patient resists carrying out the exam iner \200\231s instructions and his attempts to move or direct the limbs. 03_Semple_Chap03.indd 100 12/7/2012 6:56:50 PM DICTIONARY OF PSYCHIATRIC SYMPTOMS 101 Neologism A made-up word or normal word used in an idiosyncratic way. Neologisms are found in schizophrenic speech. Nihilistic delusions A delusional belief that the patient has died or no longer exists or t hat the world has ended or is no longer real. Nothing matters any longer and continued effo rt is pointless. A feature of psychotic depressive illness. Nystagmus Involuntary oscillating eye movements. Obsession An idea, image, or impulse which is recognized by the patient as their own, but w hich is experienced as repetitive, intrusive, and distress- ing. The return of the obsessio n can be resisted for a time at the expense of mounting anxiety. In some situations the anx iety accompanying the obses- sional thoughts can be relieved by associated compulsions (e.g . a patient with an obsession that his wife may have come to harm feeling compelled to phon e her constantly during the day to check she is still alive). Othello syndrome A monosymptomatic delusional disorder where the core delusion has the cont ent of delusional jealousy. Over-valued ideas A form of abnormal belief. These are ideas which are reasonable and under standable in themselves but which come to unrea- sonably dominate the patient \200\231s lif e. Palimpsest Episode of discrete amnesia related to alcohol or drug intoxi- cation. The indiv idual has no recall for a period when, although intoxicated, he appeared to be functioning normally. This is also commonly known as \200\230blackout \200\231, but the term palimpses t is preferable as it avoids confusion with episodes of loss of consciousness. Panic attack Paroxysmal, severe anxiety. May occur in response to a particular stimulus or occur without apparent stimulus. Paranoid delusion Strictly speaking this describes self-referential delu- sions (i.e. grand iose delusions and persecutory delusions). It is however more commonly used as a synonym fo r persecutory delusion. Paraphasia The substitution of a non-verbal sound in place of a word. Occurs in organic les ions affecting speech. Passivity phenomena Synonym for delusions of control. Persecutory delusion A delusional belief that one \200\231s life is being inter- fered with in a harmful way. Perseveration Continuing with a verbal response or action which was initially appropriate a fter it ceases to be apposite (e.g. \200\230Do you know where you are? \200\231 \200\224 \200\230in the hospital \200\231; \200\230do you know what day it is? \200\231 \200\224 \200\230in the hospital \200\231. Associated with organic brain disease and is occasionally seen in schizophrenia). Phantom mirror image Synonym for autoscopy. Phobia A particular stimulus, event, or situation which arouses anxiety in an individual an d is therefore associated with avoidance. The concept of \200\230biological preparedness \200\231 is that some fears (e.g. of snakes, \201 re, heights) had 03_Semple_Chap03.indd 101 12/7/2012 6:56:50 PM CHAPTER 3 Symptoms of psychiatric illness 102 evolutionary advantage and so it is easier to develop phobias for these stimuli than other, more evolutionarily recent threats (e.g. of guns or electric shock). Physiological dependence See Dependence. Pica The eating of things which are not food or of food items in abnormal quantities. Positive symptoms (of schizophrenia) The symptoms of schizophre- nia which are qualitativel y different from normal experience (i.e. delu- sions, hallucinations, schizophrenic thought disorder). Believed to be related to neuro-chemical abnormalities. Posturing The maintenance of bizarre and uncomfortable limb and body positions. Associated with psychotic illnesses and may have delusional sig- ni \201 cance to the patient. Pressure of speech The speech pattern consequent upon pressure of thought. The speech is ra pid, dif \201 cult to interrupt, and, with increasing severity of illness, the connection between sequential ideas may become increasingly hard to follow. Occurs in manic illness. Pressure of thought The subjective experience of one \200\231s thoughts occur- ring rapidly , each thought being associated with a wider range of conse- quent ideas than normal and wi th inability to remain on one idea for any length of time. Occurs in manic illness. Priapism A sustained and painful penile erection, not associated with sexual arousal. A rar e side-effect of antidepressant medication. If not relieved can cause permanent penile dama ge. Pseudocyesis A false pregnancy. May be hysterical or delusional in nature and can occur in both sexes although more commonly in women. The belief in the false pregnancy may be accomp anied by abdominal distension, lumbar lordosis, and amenorrhoea. Pseudodementia A presentation of severe depression in the elderly where the combination of psychomotor retardation, apparent cognitive de \201 cits, and functional decline causes di agnostic confusion with dementia. Pseudo-hallucination A false perception which is perceived as occur- ring as part of one \200\231s internal experience, not as part of the external world. It may be described as ha ving an \200\230as if \200\231 quality or as being seen with the mind \200\231s eye. Addit ionally, hallucinations experienced as true hallucinations during the active phase of a pat ient \200\231s illness may become perceived as pseudo-hallucinations as they recover. They can occur in all modalities of sensation and are described in psychotic, organic, and drug- induced conditions as well as occasionally in normal individuals. (The hallucinations of de ceased spouses commonly described by widows and widowers may have the form of a pseudo-hall ucination.) Pseudologica fantastica The production of convincing false accounts, often with apparent si ncere conviction. There may be a grandiose or over- exaggerated \202 avour to the account s produced. A feature of Munchausen \200\231s disease. 03_Semple_Chap03.indd 102 12/7/2012 6:56:50 PM DICTIONARY OF PSYCHIATRIC SYMPTOMS 103 Psychic anxiety See anxiety. Psychogenic polydipsia Excessive \202 uid intake without organic cause. Psychological dependence See Dependence. Psychological pillow A motor symptom of schizophrenia. The patient holds their head several inches above the bed while lying and can maintain this uncomfortable position for prolonge d periods of time. Psychomotor agitation A combination of psychic anxiety and excess and purposeless motor act ivity. A symptom common to many mental ill- nesses and found in normal individuals in respo nse to stress. Psychomotor retardation Decreased spontaneous movement and slowness in instigating and comp leting voluntary movement. Usually asso- ciated with subjective sense of actions being more of an effort and with subjective retardation of thought. Occurs in moderate to severe depr es- sive illness. Punding A form of stereotyped motor behavior in which there is appar- ent fascination with repetitive, mechanical tasks such as arranging items or dismantling and reassembling mechan ical objects. It is seen as a side-effect of anti-Parkinsonian medication and in some indiv iduals taking metham- fetamine. It bears some similarity to behaviors seen in individuals w ith autism. Receptive dysphasia Dysphasia affecting the understanding of speech. There is impairment in understanding spoken commands and repeating back speech. There are also signi \201 cant a bnormalities in spontaneous speech with word substitutions, defects in grammar, and syntax and neologisms. The abnormal speech so produced is however \202 uent (cf. expressive dysp hasia) and the patient may be unconcerned by his de \201 cits. Re \202 ex hallucination The experience of a real stimulus in one sensory modality trigger ing a hallucination in another. Retrograde amnesia The period of amnesia between an event (e.g. head injury) and the last c ontinuous memory before the event. Rumination A compulsion to engage in repetitive and pointless consid- eration of phrases or ideas, usually of a pseudo-philosophical nature. May be resisted for a period with consequ ent mounting anxiety. \200\230Running commentary \200\231 A type of third-person auditory hallucination which is a \201 rst-rank symptom of schizophrenia. The patient hears one or more voices providing a narrative of their current actions, \200\230he \200\231s getting up \200 now he \200 \231s going towards the window \200\231. Russell sign Skin abrasions, small lacerations, and calluses on the dorsum of the hand over lying the metacarpophalangeal and interphalangeal joints found in patients with symptoms of bulimia. Caused by repeated contact between the incisors and the skin of the hand which oc curs during self- induced vomiting. Schizophasia Synonym for word salad. 03_Semple_Chap03.indd 103 12/7/2012 6:56:50 PM CHAPTER 3 Symptoms of psychiatric illness 104 Schizophrenic speech disorder This includes the abnormalities in the form of speech consequ ent upon schizophrenic thought disorder, and those abnormalities in the use of language cha racteristic of schizophrenia such as use of neologisms and stock words/phrases. Schizophrenic thought disorder A group of abnormalities in the sub- jective description of the form of thought which occurs in schizophrenia. The abnormalities include: loosening of associations, derailment, thought blocking, fusion, and muddling. Sensory distortions Changes in the perceived intensity or quality of a real external stimul us. Associated with organic conditions and with drug ingestion or withdrawals. Examples inc lude: hyperacusis (hearing sounds as abnormally loud), micropsia ( \200\230wrong end of the telescope effect \200\231, per- ceiving objects which are close as small and far away). Snapping off Synonym for thought blocking. Somatic anxiety See Anxiety. Somatization The experience of bodily symptoms with no, or no suf- \201 cient, physical c ause for them, with presumed psychological causation. Splitting of perception Loss of the ability to simultaneously process complementary informa tion in two modalities of sensation (e.g. sound and pictures on television). Rare symptom o f schizophrenia. Stereotypy A repetitive and bizarre movement which is not goal-directed (in contrast to man nerism). The action may have delusional signi \201 cance to the patient. Seen in schizophr enia. Stock phrases/stock words Feature of schizophrenic speech disorder. The use of particular w ords and phrases more frequently than in normal speech and with a wider variety of meanings than normal. Stupor Absence of movement and mutism where there is no impairment of consciousness. Functi onal stupor occurs in a variety of psychiatric ill- nesses. Organic stupor is caused by les ions in the midbrain (the \200\230locked-in \200\231 syndrome). Synaesthesia A stimulus in one sensory modality is perceived in a fashion characteristic of an experience in another sensory modality (e.g. \200\230tasting \200\231 sounds or \200 \230hearing \200\231 colors). Occurs in hallucinogenic drug intoxication and in epileptic s tates. Tangentiality Producing answers which are only very indirectly related to the question aske d by the examiner. Tardive dyskinesia A movement disorder associated with long-term treatment with neuroleptic drugs (although it was described in psychotic patients before the use of these drugs in cl inical practice). There is con- tinuous involuntary movement of the tongue and lower face. More severe cases involve the upper face and have choreoathetoid movements of the limbs. Teleological hallucination Synonym for command hallucination. Terminal insomnia Synonym for early morning waking. 03_Semple_Chap03.indd 104 12/7/2012 6:56:50 PM DICTIONARY OF PSYCHIATRIC SYMPTOMS 105 Third-person auditory hallucinations Auditory hallucinations charac- teristic of schizophre nia where voices are heard referring to the patient as \200\230he \200\231 or \200\230she \200\231, rather than \200\230you \200\231. The \201 rst-rank symptoms of \200\230voic es heard arguing \200\231 and \200\230running commentary \200\231 are of this type. Thought blocking A symptom of schizophrenic thought disorder. The patient experiences a sud den break in the chain of thought. It may be explained as due to thought withdrawal. In the absence of such delu- sional elaboration it is not a \201 rst-rank symptom. Thought broadcasting The delusional belief that one \200\231s thoughts are accessible direc tly to others. A \201 rst-rank symptom of schizophrenia. Thought disorder See Formal thought disorder. Thought echo The experience of an auditory hallucination in which the content is the indivi dual \200\231s current thoughts. A \201 rst-rank symptom of schizo- phrenia. Also known a s gedankenlautwerden or echo de la pens e. Thought insertion The delusional belief that thoughts are being placed in the patient \200 \231s head from outside. A \201 rst-rank symptom of schizophrenia. Tic Sudden twitches of a single muscle or muscle group. Trichotillomania The compulsion to pull one \200\231s hair out. Verbigeration Repetition of words or phrase while unable to articulate the \200\230next \200\231 word in the sentence. Seen in expressive dysphasia. Verschmelzung Synonym for fusion. \200\230Voices heard arguing \200\231 A type of auditory hallucination which is a \201 r st-rank symptom of schizophrenia. The patient hears two or more voices debating with one an other, sometimes about a matter over which the patient is agonizing (e.g. \200\230he shoul d take the medication, it \200\231s worked before \200\231, \200\230no, not again, he \200 \231ll not take it this time \200\231). Vorbeigehen Synonym for Ganser symptom. Vorbeireden Synonym for Ganser symptom. Waxy \202 exibility Synonym for catalepsy. Wernicke \200\231s dysphasia A type of receptive dysphasia due to cortical lesions in or ne ar the posterior portion of the left \201 rst temporal convolu- tion (superior temporal g yrus) \200\224known as the Wernicke area. Withdrawals The physical sequelae of abstinence from a drug to which one is dependent. Thes e are individual to the drug concerned (e.g. sweat- ing, tachycardia, and tremor for alcoho l; dilated pupils, piloerection, abdominal pain, and diarrhea for opiates). Word salad The most severe degree of schizophrenic thought disorder in which no connection of any kind is understandable between sequential words and phrases the patient uses. Also c alled schizophasia. 03_Semple_Chap03.indd 105 12/7/2012 6:56:51 PM This page intentionally left blank 107 Chapter 4 Evidence-based psychiatry Introduction 108 Finding and appraising the evidence 110 Systematic reviews (SRs) of RCTs 1 12 Randomized controlled trials (RCTs) 114 Case \200\223control studies 116 Cohort studies 118 Diagnostic studies 120 Qualitative studies 122 Economic studies 124 Applying the eviden ce to patients 126 Measuring performance and implementing evidence-based practice 127 04_Semple_Chap04.indd 107 12/7/2012 6:09:00 PM CHAPTER 4 Evidence-based psychiatry 108 Introduction What is evidence-based medicine? Evidence-based medicine (EBM) is the applicat ion of research evidence to medical treatment decisions. Evidence-based practice aims to in tegrate the best available research evidence with individual clinical experience. \200 Best research evidence means the study most likely to yield an accurate and unbiased answer to a question we have about a particular patient or patient group. Clinical experience mea ns the skills we have learned during our medical training (e.g. history-taking, bedside exa mination) and also our ability to elicit our patients \200\231 preferences and goals. Key skills for evidence-based practice \200 To be able to ask a clinical question in a way that captures the essence of the \200\230pr oblem \200\231, is structured, and is most likely to yield an answer. To be able to search for an answer ( \200\230the evidence \200\231) to our question in a way that is most ef \201 cient. To be able to appraise the evidence critically. To apply the evidence to the pa tient. To monitor our own progress. \200 \200 Asking clinical questions There are generally two types of question we ask about patients: those that we ask them (fact- \201 nding questions) and questions about diagnosis, cause ( or harm), treatment, and prognosis (clinical questions). Consider the following patient sce nario: A 29-year-old woman is admitted 6wks post-partum complaining of hearing voices comme nting on her actions, and thoughts that her baby is evil. She has never sought help for psy chiatric reasons before, although her mother has long-standing bipolar disorder with many p revious hospitalizations. She does not wish to be admitted to hospital. Examples of fact- \201 nding questions include: \200 \200 \200 \200 Does she have any wish to harm her baby? Is there anyone at home who could support her? Doe s she have any symptoms of affective disorder? Is there a history of drug misuse? Examples of clinical questions include: \200 Diagnosis: what is the likelihood that the diagnosis will be schizophrenia given she descri bes a \201 rst-rank symptom of schizophrenia (running commentary)? Cause/harm: does a fam ily history of bipolar disorder increase the risk of post-partum psychosis in a relative? T reatment: is it likely that this woman would bene \201 t from the administration of ECT? P rognosis: what are the chances that the woman will harm her baby? The ability to tactfully ask fact- \201 nding questions is something taught to us as medic al undergraduates and postgraduates. There is no underlying structure to these questions an d searching the literature will not provide an answer. 04_Semple_Chap04.indd 108 12/7/2012 6:09:00 PM INTRODUCTION 109 Structuring good clinical questions Clinical questions, however, follow a standard format w hich is likely to clarify the question in your own mind, suggest a suitable study type to a ddress the problem, and more likely to yield an answer when you search for one. The general form of a question is as follows (known by the acro- nym PICO) (See Table 4.1): P: the pat ient problem to be addressed. A description of the main charac- teristics of the patient pr oblem. I: the intervention being considered (e.g. the treatment or diagnostic test being co ntemplated). May also be a harmful exposure (e.g. 10yrs of schizo- phrenia for prognosis, s moking). C: the comparison intervention (e.g. treatments) is usually compared to placebo or standard therapy; diagnostic tests are usually compared to a gold standard such as post-mo rtem, although the gold standard test in psychiatry is usually a structured clinical histor y and examination (e.g. the Structured clinical interview for DSM-IV). O: the outcome of in terest (e.g. improvement in symptoms, accurate diag- nosis, side-effects). Table 4.1 Examples of questions in the PICO format P I C O Suggest a diagnosis of schizophrenia Do \201 rst-rank symptoms Compared to full clinical examination and follow-up Diagnosis In post-partum mothers with psychosis Cause/ harm In post-partum mothers Does a family history of bipolar disorder Compared to no family history of mental illness Raise the probability of post-partum psychosis Treatment In post-partum mothers with psychosis Does ECT Compared to antipsychotic drug treatment Rapidly improve psychotic symptoms Prognosis* In post-partum mothers with psychosis After 1year What is the chance that the baby will be harmed Prognosis questions often have only three parts to their structure, unless two prognostic f actors are being compared. 04_Semple_Chap04.indd 109 12/7/2012 6:09:00 PM CHAPTER 4 Evidence-based psychiatry 110 Finding and appraising the evidence Hierarchy of evidence for therapy questions After formu lating a structured clinical question, the next step is to decide upon the study type best able to provide the answer. For a therapy ques- tion, the study types most likely to answer a question in a way that mini- mizes bias are ranked as follows: \200 A systematic review of two or more randomized controlled trials (RCTs) A single randomized controlled trial A quasi-experimental study without randomization Observational studies (e. g. cohort and case control studies) Case reports and series Expert opinion \200 \200 \200 \200 Wherever possible, a systematic review of RCTs should be sought because it is less liable t o bias than the other studies further down the hierarchy. Many people, when asked \200\230 where would you look for a study to answer your question? \200\231, will often suggest \200\230a textbook \200\231 or \200\230Medline \200\231. However, textbooks are likely to be out of date (especially for therapy) and most doctors have not been trained to use Medli ne effectively. Searching Medline (M http://www.PubMed.org) Medline can be searched by referring to the PICO structure, and by think- ing about the hie rarchy of evidence. For example, if we wish to ask our question \200\230in women with post -partum psychosis, does ECT lead to rapid improvement in symptoms when compared to antipsyc hotic drug treat- ment? \200\231, we might conduct the following search: 1: Post-partum psy chosis 2: ECT 3: 1 AND 2 4: random$ (this line will identify most RCTs in any subject) 5: 3 AND 4 Medline is organized by subject headings, but we do not need to know the subject heading to search. Medline will automatically look up a thesaurus and use more effective terms than t he ones we specify. A note on PubMed clinical queries The PubMed website has a feature called \200\230clinical queries \200\231 which searches for articles of a speci \201 c design. For exam- ple, if you search for \200\230schizophrenia \200\231 AND \200\230cognitive behavioral therapy \200\231 in the clinical queries section of PubMed, you could specify that you are only int erested in systematic reviews. Limitations of Medline Unfortunately, Medline covers only a proportion (<30%) of the psychi atric literature. Embase and PsychINFO cover a greater proportion, but are often not availa ble to health professionals because of their cost. However, many health boards in Scotland and England do have access to both Embase and PsychINFO through Athens (http://www. athens. ac.uk). You should contact your local library for details. Further training on Medline is a vailable on the PubMed website. Further EBM resources See b pp. 1018 \200\22320. 04_Semple_Chap04.indd 110 12/7/2012 6:09:00 PM FINDING AND APPRAISING THE EVIDENCE 111 Critical appraisal Critical appraisal can help us decide if a paper is likely to be valid ( i.e. the results are likely to be true) or important (i.e. contain results important for cl inical practice). The questions we should ask ourselves in order to address these two areas depend on the study type. Questions to assess the validity of a systematic review (b p. 112) \200 \200 \200 \200 Does the review address a clearly focused question? Does the review apply suitable quality criteria? Does the review search for all relevant articles? Are the results consistent from study to study? Questions to assess the validity of a RCT (b p. 114) \200 Were patients randomized to two or more treatments and was the allocation of patients to tr eatments concealed? Were patients and investigators blind to the intervention received? Wer e patients treated equally apart from the intervention of interest? Was follow-up suf \201 ciently long and complete? Were drop-outs accounted for and included in the \201 nal res ults? \200 \200 \200 Questions to assess the validity of a harm/etiology study (see Case-control studies b p. 11 6) \200 Was the exposure measured objectively? \200 Was the outcome measured objectivel y and blind to exposure status? \200 Was follow-up suf \201 ciently long and complete? \200 Did the investigators take into account any potential confounders? Questions to assess the validity of a diagnostic study (b p. 120) \200 Were the study patients similar to those on whom the test would be used in clinical practic e? Were the test and gold standard applied blind to the results of the other? Was the test applied irrespective of the results of the gold standard (and vise versa)? Questions to assess the validity of a prognosis study (see Cohort studies b p. 118) \200 Was a representative group of patients assembled at a common, preferably early, point in th eir illness? Were patients followed up prospectively for a suf \201 ciently long period? W as the outcome assessed objectively? Did the investigators correct for the presence of conf ounding? \200 \200 04_Semple_Chap04.indd 111 12/7/2012 6:09:00 PM CHAPTER 4 Evidence-based psychiatry 112 Systematic reviews (SRs) of RCTs1 Formulation of questions and protocol Questions should be pre- cise. The research designs, characteristics of participants/interventions, and outcom es should be pre-speci \201 ed. Research designs (e.g. RCT with inadequate concealment) li kely to yield biased results should be excluded, or at least noted and the effects examined in detail. Search for relevant articles The search should be comprehensive and repeatable. Should include more than Medline, as it is more likely to catalog English language, positi ve studies whilst ignoring foreign lan- guage, negative studies. Consider gray literature ( e.g. abstracts, personal communications, and others) and unpublished articles. Review of ab stracts and retrieval of full text Potentially relevant abstracts should be reviewed by 2+ reviewers with a mechanism for resolv- ing disagreements. The same applies to retrieved art icles. Proformas and pre-speci \201 ed criteria are likely to improve reliability and repe atability. Summary of included/excluded studies Reasons for exclusion and inclusion should be given to allow scrutiny/repeatability. Meta-analysis (statistical summary) Study results should be com- bined statistically, weighted for precision. \200 Heterogeneity: results vary from study to study more than expected by chance alone. Fixed e ffects analysis: assumes a single treatment effect, which is estimated by each study in an unbiased manner. Random effects analysis: doesn \200\231t assume single effect. Produces an average effect across all studies taking heterogeneity into account in the estimate of tre atment effect and its con \201 dence interval. Publication bias: the tendency for certain studies to be published according to their results. Usually, more positive results are more likely to be published. Measured using a funnel plot (see Fig. 4.1). Common statistical te sts: heterogeneity; Z test for overall effect. Effect size measurements: odds ratios \200 \224odds ratios/relative risks preferred because of statistical properties). Continuous dat a: mean difference \200\224for several studies using the same scales. Standardized effect s ize (mean difference/pooled standard deviation) \200\224for several studies using different scales \200\224 rescales the results using standard deviation of each scale allowing them to be combined (e.g. \200\230Cohen \200\231s d \200\231 and others). \2072 test for heterogeneity; Q test for dichotomous data (relative, absolute risks, 04_Semple_Chap04.indd 112 12/7/2012 6:09:01 PM SYSTEMATIC REVIEWS OF RCTS 113 \200\230Missing \200\231 studies Dots represent individual studies Increasing study size Study effect size Studies do not show effectiveness over standard treatments Studies appear to show treatment effectiveness over standard treatments Fig. 4.1 A funnel plot showing how small negative studies appear to be \200\230missing \200\231. 1 Egger M, Davey Smith G and Altman DG (eds) (2001) Systematic reviews in healthcare: meta- analysis in context. London: BMJ Books. 04_Semple_Chap04.indd 113 12/7/2012 6:09:01 PM CHAPTER 4 Evidence-based psychiatry 114 Randomized controlled trials (RCTs)1 4 Drop-out: A 5 1 2 Treat: A Outcome 3 Measurement R Treat: B Outcome 6 Drop-out: B Analysis 4 Fig. 4.2 RCTs appraisal criteria \202 owchart Appraisal criteria (see Fig. 4.2) 1 Selection of patients Are the patients typical of those on whom the drug/therapy will be us ed in practice (generalizability/external validity)? Do they differ from the average patien t in clinical practice such that we would expect (a) the results to not apply at all or (b) there to be a smaller/greater effect in clinical practice? Randomization Was the randomiza tion method adequate? Computer generated randomization by a third party on a geographically separated site at the point of entry into the trial is probably \200\230best \200\231. Wo uld it be possible for patients/clinicians to guess, better than chance, the treatment to w hich they would eventually be allocated (allocation concealment)? Has randomization succeed ed in forming two groups with similar baseline characteristics? Methods of ensuring this ar e: minimization (allocate patients to minimize differences) and strati \201 cation (strati fy randomization by important prognostic/treatment factor). Performance of interventions We re patients/clinicians/investigators/ statisticians \200\230blind \200\231 to the treatmen t? Note: There is no universally accepted meaning of blind; authors should explain what the y mean. Drop-out Was the number of drop-outs in both arms of the trial unequal (differentia l attrition) or greater than 10 \200\22320%? If so, even if the analysis takes this into ac count, the trial may be biased either to/ against the true effect size. Measurement Were al l patients analyzed in the groups to which they were randomized (intention to treat analysi s)? If not, ignoring drop- outs (completer-only analysis) may overestimate effects of treat ment. 2 3 4 5 Methods of intention to treat include: \200 \200 Last observation carried forward (assume no change in a score). Worst-case scenario (assume drop-outs in active arm have negative outcomes and drop-outs in control arm have positive ones). Mean imputation (assume drop-out was average for this group). Multiple imputations ( model mean and variance taking into account characteristics of the drop-out). \200 04_Semple_Chap04.indd 114 12/7/2012 6:09:01 PM RANDOMIZED CONTROLLED TRIALS 115 6 Analysis (see Box 4.1) If results are presented as means, typically mean differences are shown, with a t-test or analysis of variance (ANOVA) and 95% con \201 dence interval. If r esults are \200\230time to an event \200\231, then a Kaplan \200\223Meier curve (survival curve) may be shown with the results of a survival analysis (log rank test, Cox proportiona l hazards). Often the results are shown as a proportion of people with a good or bad even i n both groups (p1 and p2). The number needed to treat (NNT) is given by 1/(p1 \200\223 p2) \200\224see Box 4.1. Box 4.1 Relative risk, absolute risk, and the number needed to treat An important value to calculate from RCTs is the number needed to treat (NNT). The NNT aros e because of limitations with the terms rela- tive risk (RR) and absolute risk reduction (A RR). Imagine you have an intervention for schizophrenia: Nopixol. You locate a trial in Medline, which \201 nds the following results: 200 people with schizophrenia were randomized to p lacebo or Nopixol. 120 people received Nopixol, of which 30 relapsed at 6wks; 80 were rando mized to placebo, of which 60 relapsed over the same time. A \200\2302 \227 2 \200\231 ta ble helps to clarify the numbers: Relapse No relapse Nopixol 30 90 120 Placebo 60 20 80 The risk or probability of relapse in the Nopixol group is 30/120 or 0.25. This is called t he experimental event rate (EER). The risk or probability of relapse in the placebo group i s 60/80 or 0.75. This is called the control event rate (CER). The relative risk ( This mean s the risk of relapse on Nopixol is 0.33 times the risk on placebo. Another way of saying t his would be to say that the relative risk of relapse is reduced by 67% on Nopixol. This is sometimes called the relative risk reduction (RRR). This is usually not a good measure of clinical usefulness since if relapse was 100 times less common in both groups, the RR and R RR would stay the same. This would not re \202 ect the fact that clinically the treatment effect had diminished considerably. The absolute risk reduction ( which is 0.5. This means that for every person treated with Nopixol, the risk of relapse is reduced by about 50%. If the risk for each person is reduced by 50% by Nopixol instead of placebo, then it is intui tive that we need to treat two people to prevent, on average, one relapse. This is called t he number needed to treat (NNT). More generally, the NNT is equal to 1/ARR, or 1/0.5. In th is case the NNT = 2. RR) is the EER/CER = 0.25/0.75, which is 0.33. ARR) is the CER \200\223 EER = 0.75 \200\223 0.25, 1 Pocock SJ (1983) Clinical trials: a practical approach. Chichester: John Wiley and Sons L td. 04_Semple_Chap04.indd 115 12/7/2012 6:09:01 PM CHAPTER 4 Evidence-based psychiatry 116 Case \200\223control studies Exposed Population: with outcome Sample: outcome Not exposed Exposed Population: without outcome Sample: no outcome Not exposed Fig. 4.3 Case \200\223control studies appraisal \202 owchart Appraisal criteria (see Fig. 4.3) \200 Exposure when the outcome is rare. Cases The sample cases (those with the outcome) should i deally be a random sample of all cases from the population. Investigators should say how th e sample was selected. You should decide what effect this will have on the sorts of cases i ncluded in the study. Controls The sample controls (those without the outcome) should ideal ly be a random sample of all controls from the population and be as similar to the cases as possible (except for the exposure of interest). In practice this is dif \201 cult. Select ion of cases and controls Ideally should also be independent of exposure. For example, the selection of depressed people from a psychiatric hospital and controls from a community new sletter to assess whether child sexual abuse is associated with depression may introduce bi as because people with childhood sexual abuse are possibly more likely to be admitted to ho spital in general. Assessment of exposure objectively and blind to outcome status. In pract ice this is often dif \201 cult to accomplish as raters may be affected by their expectati ons and those with the outcome may be more likely to recall an exposure in a \200\230searc h for meaning \200\231 (recall bias). Confounding respects (apart from the exposure of inte rest), correction for this may be made in the statistical analysis. Correction should be ma de only when differences exist in a characteristic which is associated with the exposure an d outcome (e.g. age may confound an association between intravenous drug use and depression ). Case \200\223control studies are an alternative to cohort studies Measurement should be conducted Where the controls and cases differ in important 04_Semple_Chap04.indd 116 12/7/2012 6:09:01 PM CASE \200\223CONTROL STUDIES 117 Analysis from a case \200\223control study directly since the proportion of people developi ng the outcome in exposed/non-exposed populations has not been assessed. Odds ratios are of ten used and may be given, along with a 95% con \201 dence interval. A chi-square test wil l usually be used. If the investigators have examined to see if increasing levels of exposu re are more strongly associated with the outcome, a chi-squared test (for linear trend) or Mantel \200\223Haenszel test may be reported. It is not possible to calculate absolute and relative risks 04_Semple_Chap04.indd 117 12/7/2012 6:09:01 PM CHAPTER 4 Evidence-based psychiatry 118 Cohort studies Drop-out Exposed Outcome Measurement Controls Outcome Drop-out Fig. 4.4 Cohort studies appraisal \202 owchart Appraisal criteria (see Fig. 4.4) \200 Exposure strati \201 ed into levels of increasing dose. The controls should not be exposed but be similar to the exposed group. Bias will be introduced if controls differ in many wa ys apart from the exposure (e.g. drug users differ from non-drug users in many respects: em ployment, criminal record, etc.). Drop-out Drop-outs are virtually inevitable. The effects may bias the results, especially if drop-outs >20% or unequal. Some studies minimize attrit ion by consulting several sources, sending reminders, consulting government statistics (e.g . records of hospital admissions), and other methods of tracking people. Measurement status . In practice this is sometimes dif \201 cult. Retrospective/prospective notes (retrospect ively) or at interview (prospectively). Cohort studies often have retrospective and prospec tive components. Analysis then: Pa \200\223 Pb = absolute risk, pa/pb = relative risk, NNH = 1/absolute risk. If results are \200\230time to an event \200\231, then a survival anal ysis may be conducted. Correction for confounding is usually accomplished using ANCOVA, lin ear regression (outcomes measured on a scale), or logistic regression (where the outcome is an event). The exposure should be clearly de \201 ned and may be Should be conducted objectively and blind to exposure Exposure may be ascertained from case Pa,b \200\224proportion in group a or b who have the outcome, 04_Semple_Chap04.indd 118 12/7/2012 6:09:01 PM COHORT STUDIES 119 Comparing ways of measuring the importance of an intervention There are many ways in which the bene \201 t of an intervention can be measured. Cynically, one might expect the author s of an article to present the method which shows their intervention in the best light, so the reader will need to be aware of the main methods by which the utility of an interventio n can be measured and their conse- quent strengths and limitations (see Table 4.2). Table 4.2 Treatment bene \201 t Method Explanation Advantages Disadvantages Clinically insigni \201 cant treatments may still be statistically signi \201 cant. Gives little indication of precision. Provides a clear test of an investigator \200\231s hypothesis and is provided with all majo r statistical packages. P-value Gives the probability that the observed difference between the treatments is due to chance. Relative risk Gives the risk of an event in one group divided by the risk in the other group. Provides a clear indication of how many times better or worse a treatment is compared to an other.