Behaviours of concern

The terms 'challenging behaviour' (Emerson1995), and 'behaviours that challenge' (NICE 2015), are widely used in theliterature to describe behaviours such as irritability, aggression, andself‐injury. However, many behaviours seen as being challenging and framedas inherent to the person with autism could be better understood aslegitimate responses to difficult environments and situations (Ramcharan 2009). 'Challengingbehaviours', therefore, have also been described as reactive and responsivebehaviours, distressed behaviours, expressions of unmet need, and inAustralia, behaviours of concern. Throughout this review we use the term'behaviours of concern', because it is a term that is increasingly beingused internationally.

Irritability is an ambiguous term that is often not well‐defined.Irritability is defined by theDSM‐52013 as "persistent anger, a tendency to respond to events withangry outbursts or blaming others, an exaggerated sense of frustration overminor matters". Other emotions and behaviours such as anger and aggressionare often associated with irritability, however, they are usuallyconsequences of irritability rather than a trait of irritability (Benarous 2019;Toohey 2017).

In addition to the core symptoms, people with ASD may exhibit behaviours ofconcern. These can include behaviours such as agitation, aggression,self‐injury, destruction to property, disruptive behaviour, sexualmisconduct, or arson (NICE 2015;Sheehan 2015).Neurodevelopmental disorders included in the DSM‐5 such as attention deficithyperactivity disorder (ADHD), ASD, intellectual disability, specificlearning disorders, or impairments in social interaction, communication, ormovement are associated with behaviours of concern (Cleaton 2018;DSM‐5 2013), with increasing severityof disability associated with an increased likelihood, frequency, andseverity of behaviours of concern (Emerson2001;Matson 2009;McTiernan 2011).

The reported prevalence of behaviours of concern varies. It is estimated thatbetween 5% and 15% of people with ASD develop behaviours of concern (NICE 2015), with a higher prevalenceof greater than 25% reported in children (Hill 2014;Kanne 2011;Soke 2016). Prevalence tends toalso be higher in particular circumstances such as in hospitals, amongstteenagers, people in their early twenties, men and boys, people withcomorbid psychiatric diagnoses (NICE2015), and people with dual diagnoses of intellectual disabilityand ASD (Fitzpatrick 2016;Kanne 2011;Tyrer 2006).

There appears to be a high co‐occurrence of other neurodevelopmentaldisorders with ASD, such as attention deficit hyperactivity disorder (ADHD;DSM‐5 2013). People withco‐occurring ASD and ADHD may have a higher incidence of behaviours ofconcern, which is not surprising given that such behaviours are reported inboth disorders (Craig 2015;Ringer 2020). Furthermore, there isalso co‐occurrence of mental health disorders with ASD, notably anxiety anddepression (Hollocks 2019;Koritsas 2015;Lord 2018). Approximately 40% ofchildren and 27% of adults with ASD are reported to also have at least oneanxiety disorder (Hollocks 2019;Van Steensel 2011). Over 20% ofadults with ASD are reported to have a current diagnosis of depression(Van Steensel 2011). When thereare co‐occurring diagnoses, medications such as stimulants, anxiolytics orantidepressants may be prescribed to treat the co‐occurring condition.

The presence of behaviours of concern add complexity to living with andsupporting people with ASD. Not only can this result in families andinformal carers experiencing high levels of stress, they can also createbarriers to adult independence and community involvement (Smith 2014).

Antipsychotics

Antipsychotics are medications that treat disorganised thinking and poorawareness of reality. The use of antipsychotics has also been associatedwith reduced irritability, social withdrawal, hyperactivity, andstereotypical behaviours in young people with ASD (Jesner 2007). First‐generation or'typical antipsychotics' such as haloperidol were first used in the 1950s totreat people with schizophrenia. Second‐generation or 'atypicalantipsychotics' such as aripiprazole and risperidone were introduced in the1980s because of their reduced risk of long‐term and irreversible adverseeffects (AEs) when compared to typical antipsychotics. Antipsychoticmedications are psychotropic agents frequently prescribed for people withASD (Coury 2012;Howes 2018;Loy 2017;Madden 2017;Murray 2014;Rasmussen 2019), often in the absenceof a diagnosed mental disorder (Cvejic2018;Deb 2009;Deb 2015;Sheehan 2015). Large‐scale studieshave shown that around 5% to 15% of people with ASD are prescribedantipsychotics (Coury 2012;Howes 2018;Lake 2017;Murray 2014;Rasmussen 2019). Antipsychotics arecommonly prescribed for hyperactivity, aggression, and other behaviours ofconcern (Dinnissen 2020;Henderson 2020), and antipsychoticprescribing is more prevalent amongst people with autism and/or intellectualdisability compared to the general population (Glover 2015;Henderson 2020).

Although antipsychotics are not recommended for the treatment of coresymptoms of ASD (Howes 2018), thereis increasing evidence that antipsychotics decrease behaviours of concern inpeople with ASD (Howes 2018;Jesner 2007). Since publication of theprotocol for this review (Livingstone2015), seven systematic reviews reporting the effectiveness ofantipsychotics on behaviours of concern in people with autism, predominantlychildren and adolescents, have been published (D’Alò 2021;Fallah 2019;Fung 2016;Hirsch 2016;Maneeton 2018a;Maneeton 2018b;Mano‐Sousa 2021). Although resultswere mixed, the majority of evidence for the effectiveness of antipsychoticmedications in reducing behaviours of concern was reported for the atypicalantipsychotics, aripiprazole and risperidone.

There is some concern regarding the long‐term health outcomes ofantipsychotic use, such as significant weight gain (Alvarez‐Jiménez 2008;Bak 2014;Lake 2017), increased risk of diabetesmellitus (Holt 2019), increasedprevalence of cardiovascular disease such as stroke and heart attack (Zivkovic 2019), and increased risk ofall‐cause mortality (Simon 2015;Trifirò 2009). The NationalInstitute for Health and Care Excellence (NICE) Guidelines recommend thatantipsychotic medications should only be considered if behaviours of concernhave not been reduced by psychological or other interventions, treatment forany co‐existing psychiatric disorders and the person or others are at severerisk of harm (NICE 2015). Otherguidelines recommend that antipsychotics are only a short‐term option (up to8 weeks) if non‐pharmacological interventions did not reduce the behavioursof concern. Effectiveness should be reviewed after three or four weeks onthe drugs before continuing (SIGN2016), and only one drug should be trialled at any one time todetermine its effectiveness (Deb2009).

ADHD‐related medications

ADHD‐related medications are often prescribed to people with ASD who exhibitbehaviours of concern, at least in part due to some similarities between ASDand ADHD such as hyperactivity, inattention and social or communicationdeficits, or both (Cortese 2012;Hanson 2013;Mikami 2019;Rosello 2018), as well as the highcomorbidity rates of ADHD amongst people with ASD (Antshel 2013;Sokolova 2017). In the past, stimulantmedications have been prescribed to people with ASD who show behaviours ofconcern and have hyperactivity (Cortese2012;Hanson 2013;Mikami 2019;Rosello 2018). Since 2013, when a dualdiagnosis of ADHD and ASD was permitted, a high prevalence of co‐occurringASD and ADHD has been reported (Antshel2013;Sokolova 2017).Stimulants such as methylphenidate are the most commonly prescribedpsychotropic medications for people with ASD aged six years and older, withprescribing rates up to 34% reported in large multinational studies (Houghton 2017;Hsia 2014;Murray 2014), and 17% in an Australianstudy (Rasmussen 2019).

Stimulants and non‐stimulants have also been reported to reduce symptoms ofirritability and aggression in people with ASD (Banas 2020;Handen 2008;Ming 2008), and are some of the mostprescribed psychotropics for people with ASD (Madden 2017). Stimulants such asmethylphenidate, have also been recommended as adjuncts to behaviouralinterventions for hyperactivity in children or young people withco‐occurring ASD and ADHD (SIGN2016). However, a narrative synthesis byGhanizadeh 2019 concluded there wasinadequate evidence to support or refute the effect of methylphenidate onirritability, while a Cochrane Review found no evidence that rates oftreatment‐emergent irritability were different in children and adolescentswith ASD taking methylphenidate (Sturman2017).

Anticonvulsants

Anticonvulsants are primarily used to reduce seizures (Wassenaar 2013;Wlodarczyk 2012). Seizures associatedwith epilepsy are caused by abnormal and asynchronous firing of neurons(nerve cells) which usually end abruptly (DeLorenzo 2005;Geiger2011;Kusmaker 2018;Proix 2018). Mostanticonvulsants such as carbamazepine, phenobarbital and valproate blockvoltage‐gated sodium channels to reduce the firing of neurons (Verrotti 2010). Some anticonvulsantssuch as levetiracetam, topiramate or valproate also have a role in therelease or modulation of the inhibitory neurotransmitter GABA (Cortes‐Altamirano 2016), decreasingthe speed and firing of neurons. Some anticonvulsants are also used as moodstabilisers, for example, divalproex sodium, primarily in bipolar illness.Use of these medications has also been associated with reduction inaffective instability, impulsivity and aggression in ASD (Hollander 2001).

In a systematic review of anticonvulsants for psychiatric disorders inchildren and adolescents, two trials of valproate and one of levetiracetamfound no effect on aggression; however, an additional trial reported adecrease of irritability and aggression in the valproate group (Davico 2018). There was no differencein aggression in the remaining trial of participants with ASD, whichcompared to placebo. In another review of GABA modulators in autism byBrondino 2016, there was no differencein aggression and irritability in one study that evaluated valproate, whilethe other found valproate reduced irritability. Similarly, in the systematicreview of the pharmacologic treatment of severe irritability and aggressionin 2‐ to 17‐year‐olds with ASD byFung2016, one of the two small trials comparing valproate to placebofound it reduced the Aberrant Behaviour Checklist Irritability subscale(ABC‐I;Aman 1985) scores, with noapparent effect in the other.

Antidementia medications

Antidementia medications include cholinesterase inhibitors andN‐methyl‐D‐aspartate (NMDA) receptor antagonists, which are primarily usedto treat individuals with Alzheimer’s dementia. Previous studies have shownthat the cholinesterase inhibitor donepezil, has been associated withchanges in aberrant behaviours of children with ASD (Chez 2003). Research also indicatesthat the NMDA receptor antagonist, memantine, could improve socialbehaviour, self‐stimulatory behaviours (Chez 2004), and irritability (Erickson 2007), in people with ASD.

Antidepressants

Antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) andtricyclic antidepressants, are used to treat symptoms of depression,anxiety, and obsessionality and are commonly prescribed for people with ASD(Coury 2012;Howes 2018;Murray 2014); often in the absence ofa diagnosed mental disorder (Cvejic2018;Sheehan 2015;Tsouris 2013). Large‐scale studiesinvolving people with ASD have found that antidepressants are prescribed atsimilar rates to antipsychotics and stimulants, and often concurrently (upto 40%) with antipsychotics (Branford2019;Cvejic 2018;Esbensen 2009). In addition, the useof antidepressants amongst people with ASD in large‐scale studies isapproximately eight times higher than in people without ASD (Madden 2017). However, there is noclear evidence of the effectiveness of antidepressants in reducingbehaviours of concern in people with ASD (Branford 2019;Hurwitz2012;Johnco 2015;Williams 2013).

Two Cochrane Reviews evaluated the effects of these two major classes ofantidepressants on ASD. In one Cochrane Review of SSRIs for ASD (Williams 2013), there was limitedevidence that citalopram reduced irritability but no evidence thatfenfluramine and fluoxetine had an effect. In a Cochrane Review of tricyclicantidepressants for ASD in children and adolescents, there was no evidencethat clomipramine and tianeptine improved irritability relative to placebo(Hurwitz 2012); however, thethree included trials were very small. In an additional systematic review ofantidepressant and antianxiety medications for people with ASD (Deb 2021), there was no evidence thatcitalopram, clomipramine, venlafaxine or fluoxetine decreased behaviours ofconcern, but one of two trials of fluvoxamine showed reduced aggression.

Antiparkinsonian medications

Antiparkinsonian medications are primarily used to treat individuals who haveParkinson's disease and Alzheimer’s dementia. Some antiparkinsonianmedications, such as amantadine, have been studied for the treatment ofpeople with ASD to address symptoms of irritability and aggression. Adouble‐blind, placebo‐controlled trial of children with ASD aged 5 to 19years found that symptoms of irritability and aggression were reduced inthose receiving amantadine as the active medication (King 2001). Other studies havereported that they may improve language function, social behaviour, andself‐stimulatory behaviours of some people with ASD (Chez 2004). A smaller improvement inirritability symptoms has also been reported (Erickson 2007). In a systematic reviewof pharmacologic treatment in 2‐ to 17‐year‐olds with ASD (Fung 2016), there was no evidence thatamantadine decreased ABC‐I scores in the one small identifiedplacebo‐controlled trial.

Anxiolytics

As anxiety is associated with behaviours of concern (Johnco 2015;Nadeau 2011;NICE 2015), anxiolytics may beeffective in reducing behaviours of concern in people with ASD and anxiety(Bitsika 2016;Johnco 2015). Anxiolytics such asbuspirone are commonly used to treat generalised anxiety disorder (Schmitt 2005). Compared tobenzodiazepines, buspirone has a reduced risk of dependency, abuse andsedation, and so is sometimes considered a safer option for long‐termmanagement of anxiety disorders, particularly amongst the young or elderlypopulations (Crocco 2017;Schmitt 2005). Buspirone is alsoconsidered a treatment for older adults or children with aggression,irritability, or agitation (Aronson2016;Howland 2015), andas such, may be effective in reducing behaviours of concern in people withASD. In the systematic review byDeb2021, one of two parallel trials of buspirone showed a decreasein irritability.

Neurohormones

Neurohormones are hormones produced by nerve cells and secreted into thecirculation with varying mechanisms of action and sites of origin. Twoneurohormones have been investigated in ASD, namely oxytocin and secretin.Secretin has been suggested as potentially beneficial in the management ofASD and related behaviours of concern (McQueen 2002;Tanaka2018). However, in an earlier Cochrane Review of intravenoussecretin compared to placebo treatment in children or adults diagnosed withASD, there was no effect of secretin in any of the three studies thatreported irritability (Williams2012).

Experimental

Effects have previously been reported for a range of medications that do notfall into any of the previously mentioned categories. A systematic review oftrials of GABA modulators in autism evaluated acamprosate, arbaclofen,bumetanide, carnosine, flumazenil, riluzole and valproate (Brondino 2016). However, there wasinsufficient evidence to suggest that any of these medications wereeffective in people with autism (Brondino2016). In a review of the drug riluzole, which also appears toregulate glutamate activity (De Boer2019), two of three studies in children and young adults reportedthat single and adjunct use of riluzole decreased irritability, althoughthere was no effect in the remaining trial. In a meta‐analysis ofn‐acetylcysteine in ASD (Lee 2021),irritability scores were not different across all four identified studies,though a subgroup study indicated effects in one trial.

Antipsychotics

ASD has been associated with abnormalities in both the dopaminergic systemand serotoninergic systems (Nakamura2010). Dopamine over‐activation has also been linked withexcessive motor activity and stereotyped behaviours, which are oftenobserved in individuals with ASD (Previc2007). Altered serotonin levels have been found to lead tochanges in several psychological processes, which are also altered inindividuals with ASD, including mood, irritability, and aggression (Young 2002). Typical orfirst‐generation antipsychotics exert their action by blocking dopaminereceptors. However, atypical (second‐generation) antipsychotics also have arange of actions at other neurotransmitter systems, including systems thatmodulate serotonin and norepinephrine receptors.

Antidepressants

The two major classes of antidepressants prescribed for ASD (SSRIs andtricyclic antidepressants) have differing pharmacological actions. SSRIsexert their effects through increasing the availability of serotonin (Williams 2013), whereas tricyclicantidepressants increase the availability of the neurotransmitters serotoninand noradrenaline (Hurwitz 2012;Shojaie 2020). Altered serotoninlevels have been found to lead to changes in several psychologicalprocesses, which are also altered in individuals with ASD, including mood,irritability, and aggression (Young2002;Williams 2013).Antidepressants may be effective in treating some common comorbidities ofASD such as anxiety, depression, and obsessive compulsive disorder, whichcan in turn reduce behaviours of concern (Williams 2013;Zaboski2018).

Anticonvulsants

The mechanism by which antiepileptic medications, such as carbamazepine andlevetiracetam, could affect irritability and aggression remains unclear.What is known is that gabapentin reduces the excitability of nerve cells inthe brain (Guglielmo 2013).

Anticonvulsants such as divalproex sodium are also used as mood stabilisers.It has been suggested that mood stabilisers, such as divalproex sodium, workby enhancing GABA, inhibiting glutamate, acting on serotonin andnorepinephrine systems, and via limbic kindling (Hollander 2001).

ADHD‐related medications

These include stimulants such as methylphenidate and dexamphetamine thatincrease dopamine and noradrenaline activity; and non‐stimulants such asatomoxetine, clonidine and guanfacine, which primarily increasenoradrenaline activity (Osland2018).

Stimulant (Ghanizadeh 2019;Sturman 2017), and nonstimulant (Banas 2020;Ghanizadeh 2013;Patra 2019), ADHD‐related medicationshave been administered to children with ASD with the aim of improvingsymptoms. It is thought that any effects on behaviours of concern withADHD‐related medications are likely to be secondary to improvements inattention, concentration and hyperactivity (Banas 2020).

ADHD is often associated with dopaminergic system dysfunction (Froehlich 2013;Huss 2016;Wu 2012). Dopamine plays an importantrole in planning, motor and motivational processes, which are abnormal inpeople with ADHD (Marinho 2018;Wu 2012). Stimulants such asamphetamine and methylphenidate are thought to improve symptoms of ADHD byincreasing dopamine activity (Wu2012).

The neurotransmitter, noradrenaline, may also decrease symptoms of ADHD as ithas an important role in the prefrontal cortex, an area associated withattention and executive functioning (Patra2019). Non‐stimulants such as atomoxetine, clonidine andguanfacine, which primarily increase noradrenaline activity, are sometimesprescribed as an alternative to stimulant ADHD‐related medications.

Atomoxetine is a dopamine and noradrenaline reuptake inhibitor (Froehlich 2013;Janak 2012). The increase innorepinephrine and dopamine in the pre‐frontal cortex by atomoxetine isthought to improve ADHD symptoms such as impaired attention and reducedexecutive function (Patra 2019;Ulke 2019). Clonidine andguanfacine are alpha‐2 adrenergic receptor agonists (Giovannitti 2015;Huss 2016), and are thought to improveADHD symptoms by increasing noradrenergic activity in the prefrontal cortex(Caye 2019;Mechler 2022).

Antidementia medications

As described above, impairments in the dopaminergic system have beenassociated with behavioural characteristics of several neurodevelopmentaldisorders, including ASD (DiCarlo2019). Amantadine is an NMDA receptor antagonist with an indirectdopaminergic agonist role (King2001;Müller 2012).

The NMDA receptors play an important role in the cellular processes of thebrain underlying learning and memory function (Chang 2021;Olivares 2012). NMDA also plays a rolein regulating inflammation in the brain (Chang 2021), and it is thought that neuro inflammation isinvolved in neurological and neuropsychiatric disorders (Ricci 2013). The precise mechanisms bywhich NMDA receptor antagonists work is not well known, however, it has beenfound that people with ASD often have abnormally high glutamate and activitylevels of NMDA receptors (Rojas2014). Therefore, it is thought that NMDA receptor antagonists suchas memantine may play a role in reducing the core symptoms of ASD.

Antiparkinsonian medications

Cholinergic neurotransmission, including nicotinic acetylcholine receptors,are involved in several functions including attention, memory, learning,social interactions, movement, and anxiety (Park 2022;Vallés 2021).The cholinergic system is thought to play a central role in Alzheimer'sdisease, particularly the associated cognitive decline (Sabri 2008), and nicotinicacetylcholine receptors are thought to have anti‐inflammatory andneuroprotective properties (Park2022).

According to recent studies, acetylcholine and nicotinic receptor activitymay be lower in brain samples of people with ASD. It has been suggested,therefore, that acetylcholinergic enhancement through the use of donepezilhydrochloride — an acetylcholinesterase inhibitor — may improve somebehaviours associated with ASD (Chez2003).

Anxiolytics

People with ASD commonly have elevated levels of blood serotonin (Anderson 1987), however, people withASD also have an increased risk of alterations to serotonin receptors andsynthesis (Veenstra‐VanderWeele2012). Anxiolytics such as buspirone have a strong attraction toserotonin, both presynaptically and postsynaptically (Ceranoglu 2019;Poisbeau 2018), thereby increasing theavailability of serotonin. Serotonin plays a role in regulating mood andsleep, and medications that increase serotonin are often prescribed foranxiety due to the anxiolytic effect of serotonin (Żmudzka 2018).

Neurohormones

Oxytocin is produced in the hypothalamus (Wilczyński 2019), with the primary role of promoting lactation,facilitating contractions, and promoting bonding between mother and infant(Andari 2010;Green 2010;Taylor 2018). Oxytocin has been foundto be reduced in children with ASD (John2021;Moerkerke 2021),and oxytocin is thought to have a role in ASD behaviours (Gottschalk 2017;Ooi 2017;Yamasue 2017;Yoon 2020). It has been suggested thatincreasing oxytocin will reduce ASD behaviours and this could lead to areduction of behaviours of concern.

Secretin is produced in the gastrointestinal tract and has both digestive andneurological functions (Banko 2011;Welch 2004). Because secretinreceptors are also located in areas of the brain associated with emotion andbehaviour, such as in the amygdala, which regulates emotions and mood, andin the hippocampus, which is associated with memory formation (Banko 2011;Qi 2020), impairments orirregularities in brain neurohormones may be associated with ASD (Chaddad 2017;Gibbard 2018). Secretin has thereforebeen suggested as a potential intervention in the management of ASD (Krishnaswami 2011;McQueen 2002;Tanaka 2018).

Types of studies

Randomised controlled trials (RCTs), including cross‐over studies, thatcompare pharmacological interventions to an alternative drug, standard care,placebo, or wait‐list control.

Types of participants

Studies were considered eligible for inclusion if they included participantsof any age with a clinical diagnosis of ASD, who displayed one or morebehaviours of concern at baseline assessment, specifically irritability,aggression and self‐injury. People with reported comorbidities were includedin the analysis. We will also include studies that identify a subset ofpeople with ASD.

We included studies where participants were diagnosed according to thecriteria of theDiagnostic and Statistical Manual for Mental Disorders(DSM) Fourth (DSM‐IV (DSM‐41994); or DSM‐IV‐TR (DSM‐4‐TR2000)) andFifth (DSM‐5;DSM‐5 2013) Editions, or theInternational Classification ofDiseases, 10th Revision (ICD‐10;ICD‐10 2004); and those who had been diagnosed through use of astandardised diagnostic instrument, including the Autism DiagnosticObservation Schedule (ADOS;Lord2000) or the Autism Diagnostic Interview Revised (ADI‐R;Lord 1994).

Types of interventions

Any pharmacological intervention used to manage behaviours of concern inchildren, adolescents or adults with ASD, specifically irritability,aggression, or self‐injury. Interventions may have been given at any dosage,for any duration, and any frequency of administration. Relevantpharmacological interventions included first‐generation ('typical')antipsychotics such as haloperidol, second‐generation ('atypical')antipsychotics such as risperidone and aripiprazole, ADHD‐relatedmedications, anticonvulsants, antidementia medications, antidepressants(including selective SSRIs and tricyclic antidepressants), antiparkinsonianmedication, anxiolytics, neurohormones, and a number of other drugs that didnot fall into any of these classes that we grouped under an experimentalcategory.

It was possible that additional eligible interventions that review authorswere not previously aware of may be identified in the course of the review.When we identified any pharmacological interventions that were not initiallyincluded, we considered them as eligible and included them in the reviewafter assessing their comparability with those named above.

Because pharmacological interventions could be used in addition tonon‐pharmacological therapies, we included any studies in which participantsreceived concurrent non‐pharmacological therapies, provided that they wereused in all intervention arms.

The interventions of interest for this review focus on the effectiveness andbenefits and harms associated with pharmacological agents to address thebehaviours of irritability, aggression and self‐injury for people with ASD.Interventions with different foci such as sleep interventions were notincluded in this review.

Types of outcome measures

We classified outcome measures as either primary or secondary outcomes.

Lower scores indicate a more positive response for all outcomes and measuresused apart from quality of life, where higher scores indicate an improvedquality of life.

Where data were insufficient, we provided a narrative account of theoutcomes.

Where feasible, we made comparisons at the following specific follow‐upperiods:

• short‐term follow‐up (less than 6 months);

• medium‐term follow‐up (6 to 12 months); and

• long‐term follow‐up (over 12 months).

Electronic searches

We searched all available years of the following databases.

• Cochrane Central Register of Controlled Trials (CENTRAL; 2022,Issue 5), in the Cochrane Library. Searched 6 June 2022

• MEDLINE Ovid (1946 to 6 June 2022)

• MEDLINE In‐Process and Other Non‐indexed Citations Ovid (6 June2022)

• MEDLINE Epub Ahead of Print Ovid (6 June 2022)

• Embase Ovid (1974 to 6 June 2022)

• CINAHL EBSCOhost (1937 to 6 June 2022)

• APA PsycINFO Ovid (1967 to 6 June 2022)

• ERIC EBSCOhost (1966 to 6 June 2022)

• Epistemonikos (www.epistemonikos.org/en/). Searched 6 June 2022

• Sociological Abstracts Proquest, 1952 to 6 June 2022

• Science Citation Index (SCI) Web of Science Clarivate (1970 to 6June 2022)

• Conference Proceedings Citation Index – Science (CPCI‐S) Web ofScience Clarivate (1990 to 6 June 2022)

• Cochrane Database of Systematic Reviews (CDSR; 2020, Issue11), in the Cochrane Library. Searched 6 June 2022

• Database of Abstracts of Reviews of Effects (DARE), in the Centrefor Reviews and Dissemination (CRD) databases. Searched 6 June2022

• LILACS (lilacs.bvsalud.org/en/). Searched 6 June 2022

• AutismData (autism.org.uk/autismdata). Not available 6 June2022

• ClinicalTrials.gov (clinicaltrials.gov/). Searched 6 June 2022

• World Health Organization (WHO) International Clinical TrialsRegistry Platform (isrctn.com/). Searched 6 June 2022

We used search filters for RCTs where appropriate. We did not apply anylanguage or date restrictions. We did not restrict by publication status,and we sought translation of documents where necessary.

Searching other resources

We scanned bibliographies of included and excluded studies for possibleadditional references of interest.

We contacted relevant pharmaceutical companies, authors, and key scholars toidentify any additional ongoing or missed studies.

Selection of studies

Two of the four review authors (DG, MI, MJ, NL) independently selected andassessed every study at abstract and title level and then full‐text level todetermine whether they met the inclusion criteria for this review. Weresolved any disagreements between the authors through discussion with thefull review group. The selection process is presented in two PRISMA diagrams(Figure 1;Figure 2;Moher 2009).

Data extraction and management

Two review authors (DG, MI, MJ, NL) extracted data independently and enteredthem into a piloted data extraction form. We resolved any disagreementsbetween the review authors through discussion with the full review group. Weextracted the following data.

Assessment of risk of bias in included studies

Two of the four review authors (DG, MI, MJ, NL) independently assessed theseven risk of bias domains for each study and assigned each domain to one ofthe following categories as outlined in theCochrane Handbook forSystematic Reviews of Interventions (Higgins 2011):

• high risk of bias;

• low risk of bias; or

• unclear or unknown risk of bias.

When determining quality of evidence, the overall risk of bias of each trialwas assessed independently by two of the review authors and then agreed byconsensus or referral to a third review author. Assessments of risk of biasfor each study were based on the following criteria as outlined in theCochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

• Sequence generation (was the allocation sequence adequatelygenerated?)

• Allocation concealment (was allocation adequately concealed?)

• Blinding of participants and personnel (was knowledge of theallocated intervention adequately prevented during thestudy?)

• Blinding of outcome assessors (was knowledge of the allocatedintervention adequately prevented during the study?)

• Incomplete outcome data (were incomplete outcome data adequatelyaddressed?)

• Selective outcome reporting (are reports of the study free ofsuggestion of selective outcome reporting?)

• Other sources of bias (was the study apparently free of otherproblems that could put it at a high risk of bias?)

We resolved any disagreements between the review authors through discussionwith the full review group. We reached overall risk of bias judgements byconsidering the results from each relevant risk of bias domain for theoutcome being considered.

Measures of treatment effect

Unit of analysis issues

Dealing with missing data

We contacted the original investigators to request missing data. If we couldnot obtain the data, we made assumptions about whether the data appeared tobe 'missing at random' or 'not missing at random' and followed therecommendations of theCochrane Handbook for Systematic Reviews ofInterventions (Higgins2022a).

Data that are not missing at random are likely to be missing for reasonsrelated to the outcomes of the missing data. For example, if a participantagrees to take part in a trial but is unhappy with the outcome ofallocation, fails to adhere to the medication or experiences AEs as a resultof the medication, then they may be unwilling to complete any follow‐upassessments. In such a situation, where dichotomous data are missing, weimputed data on the assumption that the participants experienced the lessfavourable outcome (e.g. 'participant did not adhere to the treatment').

When studies provided insufficient information regarding the exact numbermissing from each group, data imputation was not possible, in which case weanalysed only the available data. Where continuous data were missing, weanalysed only the available data.

Where studies had missing summary data, such as missing standard deviations,we derived these where possible using calculations provided in theCochrane Handbook for Systematic Reviews of Interventions (Higgins 2022a).

We specified the methods used to address any missing data in theCharacteristics of included studiestables. If imputation was not possible, we outlined the reasons for this inthe text.

Assessment of heterogeneity

We examined clinical heterogeneity within each pairwise comparison byinspecting each included study for variability in the participants,interventions or outcomes described. We examined methodologicalheterogeneity within each pairwise comparison by inspecting each includedstudy for variability in the study design and risk of bias. We discussed infull any unexpected variability that arose. In pairwise analyses, weassessed statistically the presence of heterogeneity within each pairwisecomparison using the Chi² statistic and its P value (Deeks 2022), and the I² statistic(Higgins 2003), and its 95%CI.

Assessment of reporting biases

We assessed publication bias and other reporting biases by visuallyinspecting the funnel plots of analyses with more than 10 trials andperforming trim and fill analyses.

Data synthesis

We performed standard pairwise meta‐analyses on the results when data from atleast two included studies were available for any treatment comparison. Dueto expected heterogeneity amongst the included studies, we performed arandom‐effects meta‐analysis using an inverse variance weighting method(Chi² P value 0.05 or less) using Review Manager (RevMan) Websoftware (RevMan Web 2021). We usedan inverse‐variance approach to meta‐analysis in order to increase thecertainty of the pooled effect estimate, as larger studies with smallerstandard errors are weighted more heavily than smaller studies with largerstandard errors (Deeks 2022). Whenpooling the data was inappropriate, we provided a narrative description ofthe individual study results.

Subgroup analysis and investigation of heterogeneity

We conducted the following subgroup analyses for comparisons with asufficient number of studies that provided specific details:

• the differential effects of interventions by the age at which thedrug was first administered; for example, infant/toddler (birthto six years of age) versus school age (6 to 12 years of age)versus adolescent (12 to 18 years of age), versus adult (18years of age and over);

• the differential effects of interventions by communicationability; for example, low communication ability versus highcommunication ability;

• the differential effects of interventions by cognitive ability;for example, low cognitive ability versus high cognitiveability;

• the differential effects of interventions by the gender of theparticipant; for example, male versus female.

Because most studies did not specify the ages of children, the subgroupanalyses we conducted were children (up to 17 years of age) compared tochildren and adults, and adult‐only samples.

We also undertook subgroup analyses that were not planned in the protocol.This was because we wanted to identify whether there were differences withinsubclasses of each pharmacological class that had differing mechanisms ofaction, that is, each of the atypical antipsychotics that have differingmechanisms of action, stimulant versus non‐stimulant ADHD‐relatedmedications, SSRI versus dibenzoxazepine antidepressants, differentneurohormones, and between each of the different experimental drugs.

Sensitivity analysis

In the protocol (Livingstone 2015),we stated our aim to perform sensitivity analyses to assess whether thefindings of this review were robust to the following:

• reanalysis excluding studies according to study quality issues,including those with low sample size, high risk of bias, or highattrition;

• reanalysis without imputing data for the missingparticipants;

• reanalysis using a fixed‐effect model.

In addition, as the majority of cross‐over studies did not differentiate datafrom first and second phases, we aimed to undertake sensitivity analyses toidentify whether inclusion of these data had a differential effect onmeta‐analytic estimates.

We used the primary outcome irritability for the comparisons where there weresignificant differences between intervention and placebo groups.

We were only able to undertake sensitivity analyses on the comparisons ofantipsychotics versus placebo, and neurohormone versus placebo as there wereinadequate data for other comparisons. We were unable to do sensitivityanalyses for cross‐over studies in atypical antipsychotics as there were nocross‐over studies included in those comparisons. Also, we did not useimputed data, therefore we undertook sensitivity analysis excluding studiesat:

• high risk of attrition bias;

• high risk of other bias; and

• with a sample size less than 50.

Summary of findings and assessment of the certainty of theevidence

We created summary of findings tables using the system developed by the GRADEWorking Group (Schünemann 2013).

We usedGRADEpro GDT to import datafrom RevMan Web to create summary of findings tables for the maincomparisons and outcomes indicated under 'Types of outcome measures' (RevMan Web 2021).

Three review authors (NL, MI, DG) independently assessed the certainty of theevidence using GRADE. We resolved any disagreements through discussion.

For information regarding the GRADE approach, and factors that influence theassessment, see chapter 14 of theCochrane Handbook for SystematicReviews of Interventions (Schünemann 2022).

The main comparisons in this review as judged by clinical experts and forwhich we created summary of findings tables were as follows.

• Atypical antipsychotics versus placebo

• Neurohormones versus placebo

• ADHD‐related drugs versus placebo

• Antidepressants versus placebo

We used the following outcomes to populate the summary of findings tables forthe main comparisons.

• Irritability (short‐term)

• Aggression (short‐term)

• Self‐injury (short‐term)

• AEs (metabolic, musculoskeletal, neurological, and psychological;short‐term)

During the course of this review, many different types of AEs were found tobe reported by the included studies. To make the summary of findings tablesmore readable and useful, the clinical content experts on the review teamwere asked to prioritise the list of available AEs, to decide which shouldbe presented in the summary of findings tables. The clinical experts wereblinded to the type or availability of evidence available for each type ofAE when they made this decision, to ensure their choice was based onclinical importance and not data availability. As a result of thisprioritisation exercise, the decision was made to present a narrativesummary of the most important AEs in the four most clinically importantcategories of AEs ‐ metabolic, musculoskeletal, neurological, andpsychological.

Results of the search

An electronic search conducted in November 2020 yielded 7403 possiblereferences. This was reduced to 5002 possible references once duplicateswere removed. These 5002 references were screened at the title and abstractlevel; 4600 were irrelevant, and we excluded them for reasons such as theywere not RCTs, they used an ineligible study design, were reviews, involvedan irrelevant population or were non‐pharmacological interventions. Thisleft 402 full‐text articles (376 studies) to screen, after which we excluded76 references (as 72 studies), leaving 326 references: 281 references (121studies) included in the analysis; 26 references (22 studies) awaitingclassification; and 19 references (16 studies) for ongoing studies (Figure 1).

A top‐up electronic search was conducted in June 2022, which yielded 1809possible references. This was reduced to 1294 possible references onceduplicates were removed. After initial screening, this was reduced to 48full‐text records that needed screening, after which we excluded 12references (9 studies), leaving 36 references (as 23 studies). These were 10included studies, five studies 'awaiting classification', eight 'ongoingstudies' and 13 secondary references of these studies. SeeFigure 2 for a flow diagram of the searchprocess.

We also contacted a number of study authors to request further information.SeeTable 6 for information about the studies andcontact person.

Included studies

We have included 131 studies (291 reports and 149 datasets) involving 7014participants in this review. We identified 25 studies as awaitingclassification (seeStudies awaitingclassification) and 25 ongoing studies (seeOngoing studies). All included studiescompared a pharmacological intervention to a placebo or to anotherpharmacological intervention.

The number of participants in each study ranged from 8 to 321 and moststudies involved children, although some studies involved children andadults and some only adults; 53 studies involved only children under 13years, 37 studies involved children and adolescents, two involvedadolescents only, 16 involved children and adults, and 23 involved onlyadults.

Excluded studies

The full‐text screening resulted in 88 references (as 81 studies) beingexcluded due to ineligible criteria. Full‐text copies of the studies listedin this section were reviewed as it was not clear whether they met theinclusion criteria for the review based on title and abstract. Furtherscreening of the full‐text reports of these studies found that they did notmeet our inclusion criteria. Reasons for exclusion included: did not focuson population of interest; did not have a focus on unwanted behaviours(irritability, aggression, self‐injury); ineligible study design (non‐RCT);non‐pharmacological intervention; irrelevant comparator; and terminatedstudies.

Allocation

• Atypical or typical antipsychotics versus placebo or othertreatment: we rated 16 studies as unclear risk of biasfor randomisation and allocation concealment, mostly due to alack of details regarding methods of randomisation andallocation concealment. We rated three studies (20%) as lowbecause they conducted randomisation using a computer‐generatedcode, and one study as high due to a clear lack of randomisationand allocation concealment.

• Neurohormones versus placebo or other treatment: we rated12 studies as unclear and 12 studies as having a low risk ofbias. Studies rated as unclear either did not provide details orprovided very vague details regarding the randomisation andallocation of participants. We rated studies as low risk of biasbecause randomisation was conducted using a computer‐generatedcode.

• ADHD‐related medications versus placebo or othertreatment: we rated 10 studies as unclear risk of biasdue to a lack of details regarding methods of randomisation andallocation concealment. We rated one study as low and twostudies as high. The reason for the high ratings was because theinvestigators used 'sequential assignment'. The study rated aslow randomised using a computer‐generated method.

• Antidepressants versus placebo or other treatment: werated eight studies as unclear due to a lack of detailsregarding methods of randomisation and allocation concealment.We rated the other two studies as low risk of bias asrandomisation was conducted externally to the trial.

• Atypical antipsychotic versus another atypicalantipsychotic: we rated allocation concealment asunclear for both of the studies due to a lack ofinformation.

• Atypical antipsychotic versus an anti‐dementia drug: werated allocation concealment as unclear forNikvarz 2017 becausealthough referred to as "simple balanced blocked randomisation",the study authors did not provide information on how allocationwas concealed.

• Atypical antipsychotic versus an antiparkinsonian drug(bromocriptine): we rated allocation concealment asunclear forDollfus 1992due to a lack of information.

• Anticonvulsants versus placebo or other treatment: werated five studies as having an unclear risk of bias due to alack of details and one study as low because it conductedrandomisation using a computer‐generated code.

• Antidementia interventions versus placebo or othertreatments: we rated six studies as low risk of biasbecause they conducted randomisation using a computer‐generatedcode, and the other two studies as unclear due to a lack ofdetail regarding the allocation process.

• Antiparkinsonian interventions versus placebo or othertreatments: we rated one study as low because itconducted randomisation using a computer‐generated code and theother study as having an unclear risk of bias due toinsufficient details regarding allocation concealment.

• Anxiolytic interventions versus placebo or othertreatment: we rated one study as unclear due to a lackof details and the other study as low risk of bias because itconducted randomisation using a computer‐generated code.

• Experimental interventions versus placebo or othertreatment: we rated 24 studies as low risk of biasbecause they conducted randomisation using a computer‐generatedcode. We rated the remaining 18 studies as unclear, mainly dueto a lack of details regarding randomisation methods andallocation concealment.

Blinding

• Atypical or typical antipsychotics versus placebo or othertreatment: we rated 14 studies as unclear risk of biasdue to a lack of details regarding blinding and who was blinded,and the remaining six studies as low risk of bias.

• Neurohormones versus placebo or other treatment: we rated13 studies as unclear and the remaining 11 studies as having lowrisk of bias. Studies with an unclear risk of bias usually didnot provide further details apart from stating that they useddouble‐blinding.

• ADHD‐related medications versus placebo or othertreatment: we rated eight studies as unclear risk ofbias, three as low risk of bias and the remaining two studies ashigh risk of bias. This was due to investigators beingunblinded.

• Antidepressants versus placebo or other treatment: werated seven studies as unclear risk of bias, with the remainingthree studies at low risk of bias.

• Atypical antipsychotic versus another atypicalantipsychotic: we rated one study as a low risk of biasand the other as high due to some participants being unblindedand an unblinded clinician.

• Atypical antipsychotic versus an anti‐dementia drug: werated this study as having a high risk of bias due to being anopen‐label (randomised) study and therefore lackingblinding.

• Atypical antipsychotic versus an antiparkinsonian(bromocriptine): we rated this study as having anunclear risk of bias because it did not provide detailsregarding blinding.

• Anticonvulsants versus placebo or other treatment: werated three studies as being of low risk of bias and threestudies as unclear, mainly due to lack of details.

• Antidementia interventions versus placebo or othertreatments: we rated six studies as having low risk ofbias because they clearly stated the blinding methods that theyused, and the other two studies as unclear risk of bias due tolack of further details apart from stating the study wasdouble‐blinded.

• Antiparkinsonian interventions versus placebo or othertreatments: we rated one study as low risk of biasbecause different people were involved in the allocation ofparticipants and the measurement of outcomes. We rated the otherstudy as unclear risk of bias due to insufficient detailsregarding blinding.

• Anxiolytic interventions versus placebo or othertreatment: we rated one study as low risk of biasbecause an external person, who was not involved in enrolment orallocation, monitored outcomes. We rated the other study asunclear risk of bias because although the study stated that theyused double‐blinding, the person who allocated participants togroups was unblinded.

• Experimental interventions versus placebo or othertreatment: we rated 30 studies as low risk of bias, 11as unclear, and one as high risk of bias due to the use ofsingle‐blinding only. The studies rated as unclear were due to alack of details regarding blinding and who was blinded, and thehigh risk of bias was because the assessors were unblinded.

Incomplete outcome data

• Atypical or typical antipsychotics versus placebo or othertreatment: we rated 12 studies at low risk of bias, witha further four studies being rated as unclear and four studiesas high risk of bias due to high rates of attrition, notincluding some participants in the analysis due to lack ofefficacy, or lack of details regarding participants lost tofollow‐up. We rated studies as unclear due to vague detailsregarding imputation of missing data, or an intention‐to‐treatanalysis that did not include all participants.

• Neurohormones versus placebo or other treatment: we rated13 studies as low, six studies as unclear and five as high riskof bias. Studies rated as high had up to 50% missing data or didnot provide reasons for loss to follow‐up. Studies rated asunclear did not provide reasons for participants lost tofollow‐up, or some participants were not accounted for inanalysis or numbers of participants lost to follow‐up. Studiesrated as low had included all participants in the analysis andused an intention‐to‐treat analysis for any participants who didnot complete the trial.

• ADHD‐related medications versus placebo or othertreatment: we rated five studies as unclear, two as lowand six as high. We judged studies as high risk due tounexplained loss to follow‐up, incomplete data or lack ofpost‐baseline ratings. Ratings of unclear were because the studyauthors did not clearly report numbers of participants whocompleted the study and any who were lost to follow‐upthroughout the study. Studies with ratings of low had includedall participants in the final analysis or used anintention‐to‐treat analysis, or both.

• Antidepressants versus placebo or other treatment: werated four studies as having an unclear risk of bias, threestudies as high and three studies as low risk of bias. 'Unclear'ratings were because it was not clear how many participants wereincluded in the analysis, or loss to follow‐up was not reportedby group. Reasons for a judgement of high risk of bias includedhigh attrition of 20% to 25%, and not providing reasons forparticipant loss to follow‐up. The studies rated as low risk ofbias used an intention‐to‐treat analysis and included allparticipants in the final analysis.

• Atypical antipsychotic versus another atypicalantipsychotic: we rated both studies as having a lowrisk of bias as all participants were included in theanalysis.

• Atypical antipsychotic versus an anti‐dementia drug: werated the study as high risk of bias because data were notimputed for participants who discontinued.

• Atypical antipsychotic versus an antiparkinsonian(bromocriptine): we rated the study as having a low riskof bias because only one participant did not complete the study,and it used a last observation carried forward.

• Anticonvulsants versus placebo or other treatment: werated three studies as unclear risk of bias and three studies ashigh risk of bias. The ratings of unclear were mainly due tounaccounted for participants, not imputing data whereparticipants were lost to follow‐up, or lack of clarityregarding the number included in the analysis. The studies ratedas high risk of bias were because of incomplete data.

• Anti‐dementia interventions versus placebo or othertreatments: we rated six studies as having low risk ofbias, one study as high and one study as unclear risk of bias.The study with a high risk of bias had almost 50% attrition andthe study rated as unclear provided vague details regarding lossto follow‐up and number analysed. Studies rated as low risk ofbias included all participants in the analysis and used anintention‐to‐treat analysis for any participants who did notcomplete the trial.

• Antiparkinsonian interventions versus placebo or othertreatments: we rated one study as low risk of biasbecause all participants were included in the analysis, while werated the other study as unclear due to imputation using lastobservation carried forward for all participants with at leastone measurement post‐baseline.

• Anxiolytic interventions versus placebo or othertreatment: we rated one study as unclear and the otherstudy as high risk of bias. The high risk of bias was due to notreporting outcome data at one of the prespecified time pointsand the study rated as unclear was due to "unavailable data" foralmost half of the discontinued participants.

• Experimental interventions versus placebo or othertreatment: we rated 17 studies as low risk of bias, 14as unclear and 11 studies as high risk of bias. The studiesrated at high risk of bias were mainly due to significantattrition or not reporting reasons for loss to follow‐up. Theratings of unclear were because it was unclear how many wereincluded in the analysis, or no further statistical measuressuch as intention‐to‐treat were used for those lost tofollow‐up.

Selective reporting

• Atypical or typical antipsychotics versus placebo or othertreatment: we rated nine studies as high risk of bias,seven studies as low and four studies as unclear risk of bias.We rated the nine studies as high because of incomplete orabsent reporting of outcomes, and not reporting AEs when it ishighly likely they would have occurred. The studies rated as lowwere because all outcomes listed in the protocol or on the trialregistry were reported in the published paper. The unclearratings were due to lack of a protocol.

• Neurohormones versus placebo or other treatment: we rated11 studies as low risk of bias because outcomes reported matchedthose listed in the protocol, seven studies as unclear due to anabsence of a published protocol or trial registration, and sixas high risk of bias. Studies rated as high risk of bias did notreport outcomes that were mentioned or listed on the clinicaltrials registry.

• ADHD‐related medications versus placebo or othertreatment: we rated seven studies as high risk of bias,three studies as low and two were unclear. The reasons for thehigh ratings were either incomplete or absent outcome data. Theratings of unclear were because of the absence of a publishedpaper and details only provided on the trial registry. Theratings of low were because all outcomes listed in the protocolor on the trial registry were reported in the publishedpaper.

• Antidepressants versus placebo or other treatment: werated four studies as low risk of bias, four studies as unclearand two studies as high risk of bias. Reasons for a rating ofhigh were incomplete or absent outcome data. We rated studies aslow because all outcomes listed in the protocol or on the trialsregistry were reported in the published paper. The unclearratings were because of an absence of a published paper anddetails only provided on the trial registry.

• Atypical antipsychotic versus another atypicalantipsychotic: we rated one study as having a high riskof bias, due to conflicting statements that disagree with thestatistics that they provided, and the other study as low riskof bias.

• Atypical antipsychotic versus an antidementia drug: werated this study as having an unclear risk of bias due to lackof a protocol.

• Atypical antipsychotic versus an antiparkinsonian(bromocriptine): we rated this study as having anunclear risk of bias due to lack of a protocol.

• Anticonvulsants versus placebo or other treatment: werated five studies as high risk of bias and one as low risk. Theratings of high risk of bias were due to lack of outcome data,the use of P values or t‐values to report data, or differencesbetween information in published papers and the clinical trialsregistry. The rating of low was because outcomes reportedmatched those listed in the protocol or on the trialsregistry.

• Antidementia interventions versus placebo or othertreatments: we rated three studies as having a high riskof bias, four studies as low and one study as having an unclearrisk of bias. The unclear rating was because of an absence of apublished protocol, and the low ratings were because alloutcomes listed in a protocol or trial registry were reported bythe study authors in the published paper. The ratings of highwere because outcome data were not reported.

• Antiparkinsonian interventions versus placebo or othertreatments: we rated one study as low risk of bias andthe other as unclear because it used last observation carriedforward for any participant with at least one post‐baselinemeasure.

• Anxiolytic interventions versus placebo or othertreatment: we rated one study as low risk of biasbecause all outcomes listed in a protocol or trial registry werereported by the study authors in the published paper, and thestudy rated as high risk of bias was due to outcome measures notreported at the time points mentioned.

• Experimental interventions versus placebo or othertreatment: we rated 21 studies as low risk of biasbecause outcomes reported matched those listed in the protocol,12 as unclear due to an absence of a published protocol or trialregistry, and nine studies as high. The reasons for high risk ofbias were failure to report outcomes mentioned in protocols oron trial registries, or reporting data at different time pointsto that mentioned in the protocol or trial registry.

Other potential sources of bias

• Atypical or typical antipsychotics versus placebo or othertreatment: we rated six studies as low risk of bias,eight as high risk of bias, and six as unclear. Most of thestudies rated as high risk of bias were because of funding orother support by pharmaceutical companies, agreements betweenstudy authors and sponsors regarding the publishing of results,a small proportion of the sample with a diagnosis of autismdespite the title mentioning autism spectrum disorder, or studyauthors' direct involvement in the ethics committee or fundingprocess. The studies rated as unclear were because of somefinancial or other support from pharmaceutical companies. Thesix studies rated as low were because we identified no othersources of bias.

• Neurohormones versus placebo or other treatment: we ratednine studies as high risk of bias, 10 as low and five studies asunclear risk of bias. All studies rated as high risk of biaswere either funded by pharmaceutical companies, thepharmaceutical companies were involved in the analysis, orparticipants were responders to the intervention in a previoustrial. Studies rated as low were because we did not identify anyother sources of bias, and the studies rated as unclear were dueto some involvement by pharmaceutical companies in thestudy.

• ADHD‐related medications versus placebo or othertreatment: we rated five studies as high risk of biasdue to a lack of standardised measures, having received fundingby pharmaceutical companies, or study authors' directinvolvement in the ethics committee or funding process. We ratedfive studies as unclear due to highly divergent samples inaddition to small sample sizes or lack of details regardingsponsorship or funding, and three studies as low because we didnot identify any other sources of bias.

• Antidepressants versus placebo or other treatment: werated five studies as unclear risk of bias because of lack ofdetails regarding funding, a published paper not beingavailable, or a lack of baseline comparisons reported by group.We rated one study as low and four as high risk of bias. Werated studies as high risk of bias due to involvement oremployment of study authors by pharmaceutical companies, studyauthors' direct involvement in the ethics committee or fundingprocess, or an imbalance in baseline characteristics between thetwo groups. The one study rated as low was because we did notidentify any other sources of bias.

• Atypical antipsychotic versus another atypicalantipsychotic: we rated both studies as having a lowrisk of bias because we did not identify any other sources ofbias.

• Atypical antipsychotic versus an antidementia drug: werated this study as having a low risk of bias because we did notidentify any other sources of bias.

• Atypical antipsychotic versus an antiparkinsonian(bromocriptine): we rated this study as having anunclear risk of bias because we did not identify any othersources of bias. However, without a protocol or trial registryentry, it is difficult to know.

• Anticonvulsants versus placebo or other treatment: werated three studies as unclear risk of bias, two as high and oneas low risk of bias. The studies rated as unclear were due tofunding or other support from pharmaceutical companies, and thestudies rated as high were due to a change in study durationwithout explanation or study authors' direct involvement in theethics committee or funding process. The study rated as low wasbecause we did not identify any other sources of bias.

• Antidementia interventions versus placebo or othertreatments: we rated one study as a low risk of biasbecause we did not identify any other sources of bias. We ratedseven studies as high risk of bias due to funding and otherinvolvement by pharmaceutical companies or study authors' directinvolvement in the ethics committee or funding process.

• Antiparkinsonian interventions versus placebo or othertreatments: we rated one study as unclear risk of biasdue to pharmaceutical companies providing funding and theunknown role they may have had in the study. We rated the otherstudy as high risk of bias due to study authors' directinvolvement in the ethics committee or funding process.

• Anxiolytic interventions versus placebo or othertreatment: we rated one study as unclear and the otheras a high risk of bias because the study was retrospectivelyregistered on the clinical trials website.

• Experimental interventions versus placebo or othertreatment: we rated six studies as low risk of biasbecause we did not identify any other sources of bias, sixstudies as unclear and 30 studies as high risk of bias. Thereasons for high risk of bias were funding or other involvementby pharmaceutical companies in the studies, study authors beingemployed by the pharmaceutical companies funding the study, orstudy authors' direct involvement in the ethics committee orfunding process. The reasons for an unclear rating were becauseof some involvement of pharmaceutical companies, or studyauthors did not provide baseline details regarding groupdifferences.

Atypical antipsychotics versus placebo

Neurohormones versus placebo

Comparison 3: ADHD‐related medications versus placebo

Antidepressants versus placebo

Atypical versus typical antipsychotics

Atypical antipsychotics versus atypicalantipsychotics

Atypical antipsychotics versus antidementiamedications

Atypical antipsychotics versus antiparkinsonians

Anticonvulsants versus placebo

Antidepressants versus antidepressants

Antidementia interventions versus placebo or othertreatment

Antiparkinsonian medications versus placebo or othertreatment

Anxiolytic interventions versus placebo or othertreatment

Experimental interventions versus placebo or othertreatment

Typical antipsychotics versus placebo

Sensitivity analyses

Where we had sufficient data, we carried out sensitivity analyses onirritability data excluding studies at:

• high risk of attrition bias;

• high risk of other bias; and

• with a sample size less than 50.

Antipsychotics

At short‐term follow‐up (up to 6 months), atypical antipsychotics comparedwith placebo probably reduce irritability (moderate‐certainty evidence) andmay also reduce self‐injury (low‐certainty evidence). However, there was noclear evidence of a difference in aggression between groups (verylow‐certainty evidence) in participants with ASD. Some AEs may be higher inparticipants who receive atypical antipsychotics. These include theneurological AEs of dizziness, fatigue, sedation, somnolence, and tremor(low‐certainty evidence), the metabolic AE of increased appetite(low‐certainty evidence), and the gastrointestinal AEs of abdominal pain,constipation, drooling, hypersalivation, and vomiting or nausea, but therewas no clear evidence of a difference between groups for any of the otherAEs.

Studies that investigated typical antipsychotics reported only self‐injury,with no clear evidence of a difference compared to placebo in the shortterm. Similarly, the two trials of typical antipsychotics versus placeboshowed no clear differences in reported musculoskeletal, neurological orpsychological AEs.

There was no clear evidence of a difference between typical and atypicalantipsychotics on behaviours of concern or AEs.

Neurohormones

Eight studies reported irritability (466 participants). There was minimal tono clear evidence of a difference in irritability in the short term whenneurohormones were compared to placebo (very low‐certainty evidence). Noneof the neurohormone studies reported aggression or self‐injury.

Neurohormones may reduce the risk of headaches (very low‐certainty evidence)but there were no clear differences between groups for any of the otherneurological AEs. Neurohormones may decrease the rates of vomiting(low‐certainty evidence), but there were no clear differences between groupsfor any other gastrointestinal AEs. There were no clear differences betweengroups for any metabolic or psychological AEs (low‐certainty evidence), ormusculoskeletal AEs (very low‐certainty evidence).

ADHD‐related medications

At short term follow‐up, ADHD‐related medications may reduce irritabilitywhen compared to placebo (low‐certainty evidence). There was no clearevidence of a difference in self‐injury between those receiving ADHD‐relatedmedications compared to a placebo (very low‐certainty evidence). No datawere reported for aggression.

We found very uncertain evidence that participants who receive ADHD‐relatedmedications have higher rates of AEs compared to those who receive placebo.ADHD‐related medications may increase rates of drowsiness,emotion/tearfulness, fatigue, headache, insomnia, and irritability (verylow‐certainty evidence) but there was no clear difference between groups forother neurological AEs: dizziness, motor tics, agitation, repetitivebehaviour, or restlessness. ADHD‐related medications may increase rates ofdepression (very low‐certainty evidence) but there were no clear differencesbetween groups for any of the other psychological AEs. ADHD‐relatedmedications may lead to higher rates of decreased appetite (verylow‐certainty evidence) but there were no clear differences between groupsfor the metabolic AEs of increased appetite or increased motor activity(very low‐certainty evidence). ADHD‐related medications may increase ratesof constipation, dry mouth, and stomach or abdominal discomfort, but therewere lower rates of diarrhoea in the ADHD‐related medication group comparedto placebo. None of the studies in this comparison reported musculoskeletalAEs.

Antidepressants

At short‐term follow‐up, there was no clear evidence of a difference inirritability between those receiving antidepressants and those receivingplacebo (low‐certainty evidence). Data for aggression and self‐injury wereeither not reported or could not be included in the analysis.

Antidepressants may lead to higher rates of decreased attention(low‐certainty evidence), but there was little to no difference betweengroups for the other neurological AEs. Antidepressants may increase rates ofimpulsive behaviour and stereotypy (very low‐certainty evidence) but therewere no clear differences between groups for any of the other psychologicalAEs (very low‐certainty evidence). Antidepressants may increase the rates ofdecreased energy (very low‐certainty evidence) but there were no cleardifferences between groups for any of the other metabolic AEs. There were noclear differences between groups for any musculoskeletal AEs (verylow‐certainty evidence).

Antipsychotics

Since the protocol for this review was published, seven systematic reviews ofthe effectiveness of antipsychotics in people with autism, predominantlychildren and adolescents, and reported behaviours of concern were published(D’Alò 2021;Fallah 2019;Fung 2016;Hirsch 2016;Maneeton 2018a;Maneeton 2018b;Mano‐Sousa 2021), in addition to thereview byJesner 2007. Theseincluded network meta‐analyses (Fallah2019), meta‐analyses and narrative syntheses. Five of thesesystematic reviews were on the effectiveness of atypical antipsychotics, onesystematic review was on multiple drug classes (Fung 2016), and the other review wason both typical and atypical antipsychotics (D’Alò 2021). All of these reviewsinvolved children and adolescents, and the outcomes included irritabilityusing the ABC‐I subscale (all reviews), aggression (Fung 2016), and AEs (all reviews).Across these reviews, as with our current review, there was evidence for theeffectiveness of aripiprazole and risperidone in reducing irritability.

However, as with this current review, there was evidence for AEs across arange of systematic reviews. This included an overall increase (Alfageh 2019;D’Alò 2021), but also increasedserious adverse events (D’Alò 2021),in children and adolescents with ASD.

Mean weight was also higher in trials of olanzapine, risperidone andaripiprazole (Fallah 2019;Fung 2016;Jesner 2007;Hirsch 2016;Maneeton 2018a;Mano‐Sousa 2021). Systematic reviewsalso found that haloperidol, risperidone, and aripiprazole were associatedwith somnolence or sedation (Fung2016;Hirsch 2016;Maneeton 2018a;Maneeton 2018b). Extrapyramidalsymptoms were also increased in the review byFung 2016; and hypersalivation in thereview byManeeton 2018b.

Neurohormones

We found that neurohormones may have a minimal to small effect on behavioursof concern (irritability). In the Cochrane Review of intravenous secretincompared to a placebo treatment in children or adults diagnosed with ASD,there was no effect of secretin in any of the three studies that reportedirritability (Williams 2012).

ADHD‐related medications

The current review found that there was low‐certainty evidence that overallADHD‐related medications decreased irritability. Findings from two previousreviews did not find evidence that ADHD medications had an effect onirritability. A narrative synthesis byGhanizadeh 2019 of clinical trials of stimulants in children andadolescents with both autism and ADHD, concluded inadequate evidence tosupport or refute their effect on irritability. While a Cochrane Review bySturman 2017 found thatmethylphenidate did change reports of irritability that were reported as AEsin children and adolescents with ASD.

Antidepressants

We found no clear differences between antidepressants and placebo inbehaviours of concern and this seems to be in line with previous evidencefrom trials of antidepressants.

In the Cochrane Review of SSRIs for ASD there was no evidence thatfenfluramine and fluoxetine had an effect, and only limited evidence thatcitalopram reduced irritability (Williams2013). In addition, citalopram and fenfluramine were associatedwith increased AEs.

A Cochrane Review of tricyclic antidepressants for ASD in children andadolescents also found no evidence that clomipramine or tianeptine improvedirritability, although clomipramine was associated with cardiac andneurological AEs, and tianeptine with sedation (Hurwitz 2012).

A more recent systematic review byDeb2021, found no evidence that citalopram, clomipramine,venlafaxine or the SSRI fluoxetine decreased behaviours of concern, thoughone of two trials of fluvoxamine reduced aggression.

Anticonvulsants

As with our findings, there is little evidence that anticonvulsants decreasebehaviours of concern. In a systematic review of anticonvulsants in childrenand adolescents byDavico 2018,there was limited evidence of valproate having an effect on irritability andaggression in a single trial at 12 but not eight weeks, and no evidence thatlevetiracetam had any effect. In the narrative review byBrondino 2016 there were mixedfindings with one of two trials finding no effect of valproate on aggressionand irritability, while the other reported that valproate reducedirritability. Similarly, one of the two trials in the systematic review byFung 2016 reported thatvalproate decreased irritability with no apparent effect in the othertrial.

The review of valproate use inBrondino2016 also reported mild side effects but no serious adverseevents were reported. The review byFung2016 also reported that valproate was associated with weightgain.

Antiparkinsonians

As with the current review, there was no evidence that antiparkinsoniansdecreased behaviours of concern compared with placebo. The systematic reviewbyFung 2016 found no evidence thatamantadine decreased irritability in the one small placebo‐controlled trial,and amantadine was also associated with somnolence and sedation.

Anxiolytics

A recent review showed contradictory findings for the effectiveness ofanxiolytics on behaviours of concern. In the systematic review byDeb 2021, only one of two trials ofbuspirone showed a decrease in irritability. No major adverse events werereported, with the most common adverse events being changes in appetite,drowsiness, and fatigue.

Experimental

Systematic reviews were identified for several individual drugs or drugclasses that we categorised as experimental for the purposes of this review.They were reviews of the GABA modulators acamprosate, arbaclofen,bumetanide, carnosine, flumazenil, riluzole and valproate in autism reviewedbyBrondino 2016 (the findings withvalproate are discussed under anticonvulsants); a review of riluzole byDe Boer 2019; and a review ofn‐acetylcysteine byLee 2021.

As with our findings, in the systematic review byBrondino 2016, the authors concludedthat there was insufficient evidence to suggest the use of the GABAmodulators in autism. Though a later review of riluzole byDe Boer 2019 found that riluzoledecreased irritability in one trial with no apparent effect in the othertrial.

In the meta‐analysis of N‐acetylcysteine byLee 2021, there was no effect across all four identified studiesin ASD, although mild AEs were reported. This was in line with our findingsin this review.

Based on data from all identified trials, atypical antipsychotics(risperidone and aripiprazole) appear to reduce behaviours of concern inpeople with autism spectrum disorder (ASD) by approximately 34% andattention deficit hyperactivity disorder (ADHD)‐related medications byapproximately 32% in the short term. However, there was also evidencethat certain adverse effects (e.g. sedation and weight gain) may beassociated with their use. Consideration should be given to whetherprescribing and administration is warranted given the risk of adverseevents. There were inadequate data to draw conclusions about theireffectiveness in the medium or long term.

There was little to no evidence of an effect of anticonvulsants,antidepressants, anxiolytics, antidementia medications, antiparkinsonianmedications, neurohormones, or 'experimental' interventions onbehaviours of concern (irritability, aggression or self‐injury) in theshort term. In addition, there was little to no evidence of a differencein adverse effects between these intervention groups and placebo groups.There were inadequate data to draw conclusions about their effectivenessin the medium or long term.

Before considering medications to manage a person’s behaviour of concern,a comprehensive assessment to gain a functional understanding of theirbehaviours should be undertaken and non‐pharmacological interventionstrialled, which supports the National Institute for Health and CareExcellence (NICE) guidance on interventions for people with intellectualdisability and behaviours of concern (NICE 2015). In addition, clinicians should seek informedconsent to use medications to manage behaviour from the person, or theirsubstitute decision maker, and should discuss with them the risks andbenefits associated with these medications to ensure that they areclearly understood.

Length of follow‐up emerged as a major theme in the included studies,with only 12 studies following up participants for more than threemonths, one of which followed up participants for more than six months.This highlights the need for studies of longer than six months' durationto identify the long‐term health effects of pharmacologicalinterventions in people with ASD.

Another major theme to emerge is the lack of studies involving adults;only 23 of 131 trials included adults as the target population. Thishighlights the need for more studies with adults to identify theeffectiveness and adverse effects associated with pharmacologicalintervention use amongst adults with ASD and behaviours of concern.

A total of 95 (72%) of the included studies across all comparisonsreported irritability as an outcome, whereas only four studies reportedaggression and only 13 studies reported self‐injurious behaviour. Thishighlights the need for more studies to measure 'behaviour of concern'outcomes. Further, only 10 studies reported the outcome of quality oflife. In addition, the consistent use of validated scales for each ofthese outcomes is important.

Adverse effects were reported by 110 (83%) of the studies, however, theinconsistency in reporting of adverse effects has highlighted the needfor the use of consistent and validated scales particularly in relationto adverse effects associated with antipsychotic use. Consistent use ofa validated adverse effect scale may lead to greater consistency inreporting and increase the relevance and usability of outcome data.

We downgraded certainty of evidence for most of the comparisons due tosmall sample sizes, as many of the studies included in this reviewinvolved fewer than 50 participants. Future studies should aim toinvolve at least 100 participants to increase the certainty of theevidence.

CENTRAL

#1 [mh "child development disorders, pervasive"]
#2 [mh ^"DevelopmentalDisabilities"]
#3 [mh ^"Neurodevelopmental disorders"]
#4(pervasive NEAR/3 child*)
#5 pervasive NEXT development* NEXTdisorder*
#6 (PDD or PDDs or PDD NEXT NOS or ASD or ASDs)
#7autis*
#8 asperger*
#9 kanner*
#10 childhood nextschizophrenia
#11 Rett*
#12 {OR #1‐#11}
#13 [mh ^"Drugtherapy"]
#14 ((pharma* or drug) NEAR/1 (intervention* or therap* ortreat*))
#15 pharmacotherap*
#16 [mh^Psychopharmacology]
#17 (psychopharmacol* or psycho nextpharmacol*)
#18 [mh ^"Off‐Label Use"]
#19 (off next label)
#20 (novel NEAR/1 (drug* or medication* or pharma* ortreatment*))
#21 (acetylcholinesterase or acetyl NEXTcholinesterase)
#22 [mh ^Amisulpride]
#23 (Analeptics or(Analeptic near agent*) or (Analeptic near drug*))
#24 [mh^"Anti‐Anxiety Agents"]
#25 (anxiolytic* or antianxiety NEXT agent* orantianxiety NEXT drug* or anti NEXT anxiety NEXT agent* or anti NEXT anxietyNEXT drug*)
#26 [mh Anticonvulsants]
#27 (Anticonvulsant* oranti next convulsant*)
#28 (antiepileptic* or anti nextepileptic*)
#29 [mh "Antidepressive Agents"]
#30 (antidepress*or anti NEXT depress*)
#31 [mh "Antipsychotic Agents"]
#32(antipsychotic* or anti next psychotic*)
#33 [mh "AntihypertensiveAgents"]
#34 [mh "Antiparkinson Agents"]
#35 (antiparkinson oranti next parkinson)
#36 [mh ^"Adrenergic UptakeInhibitors"]
#37 [mh ^"Atomoxetine Hydrochloride"]
#38 [mhBromocriptine]
#39 [mh Buspirone]
#40 [mh "Central NervousSystem Stimulants"]
#41 (CNS or central next nervous) nextStimulant*
#42 [mh "Cholinesterase Inhibitors"]
#43Cholinesterase next Inhibitor*
#44 [mh citalopram]
#45 [mhClomipramine]
#46 [mh Clonidine]
#47 [mh Fluoxetine]
#48[mh Fluvoxamine]
#49 [mh guanfacine]
#50 [mhHaloperidol]
#51 [mh Imipramine]
#52 [mhLevetiracetam]
#53 [mh "Lurasidone Hydrochloride"]
#54 [mhmemantine]
#55 [mh methylphenidate]
#56 [mhMilnacipran]
#57 mood next stabili*er*
#58 (neurohormone* orneuro NEXT hormone*)
#59 (NMDA NEAR/1 (antagonist* orreceptor*))
#60 [mh Nortriptyline]
#61 [mh oxytocin]
#62[mh Olanzapine]
#63 [mh "Paliperidone Palmitate"]
#64 [mhParoxetine]
#65 [mh "Quetiapine Fumarate"]
#66 [mhRisperidone]
#67 [mh Rivastigmine]
#68 [mh Secretin]
#69[mh "Serotonin and Noradrenaline Reuptake Inhibitors"]
#70 [mh"Serotonin Uptake Inhibitors"]
#71 ((Serotonin NEAR/3 Uptake NEXTInhibitor*) or (Serotonin NEAR/3 reuptake NEXT Inhibitor*) or (SerotoninNEAR/3 re NEXT uptake NEXT Inhibitor*))
#72 (SSRI or SSRIs)
#73[mh Sertraline]
#74 Tetracyclic*
#75 [mh Topiramate]
#76Tricyclic*
#77 [mh "Venlafaxine Hydrochloride"]
#78 [mh"Valproic Acid"]
#79 (amantadine or amisulpride or aripiprazole oratomoxetine or bromocriptine or buspirone or Centedrin or Concerta orDaytrana or citalopram or clomipramine or clozapine or divalproex ordonepezil or Equasym or escitalopram or fluoxetine or fluvoxamine orgabapentin or guanfacine or Haloperidol or imipramine or iamotrigine orlamotrigine or levetiracetam or lurasidone or memantine or Metadate orMethylin or Methylphenidat* or milnacipran or mirtazapine or nortriptylineor olanzapine or oxytocin or paliperidone or paroxetine or Phenidylate orquetiapine or risperidone or Ritalin* or rivastigmine or secretin orSertraline or Tianeptine or Topiramate or Tsentedrin or valproate orVenlafaxine or Ziprasidone)
#80 {or #13‐#79}
#81 #12 and #80 inTrials

Ovid MEDLINE

1 exp child development disorders, pervasive/ 
2 DevelopmentalDisabilities/ 
3 Neurodevelopmental disorders/ 
4 pervasivedevelopment$ disorder$.tw,kf. 
5 (pervasive adj3child$).tw,kf.
6 (PDD or PDDs or PDD‐NOS or ASD or ASDs).tw,kf.
7 autis$.tw,kf. 
8 asperger$.tw,kf. 
9 kanner$.tw,kf.
10 childhood schizophrenia.tw,kf. 
11 Rett$.tw,kf. 
12or/1‐11
13 Drug Therapy/ 
14 ((pharma$ or drug) adj1(intervention$ or therap$ or treat$)).tw,kf. 
15pharmacotherap$.tw,kf. 
16 Psychopharmacology/
17(psychopharmacol$ or psycho‐pharmacol$).tw,kf. 
18 "Off‐Label Use"/
19 (off label or "off‐label").tw,kf.
20 (novel adj1 (drug$ ormedication$ or pharma$ or treatment$)).tw,kf. 
21(acetylcholinesterase or acetyl‐cholinesterase).mp. 
22 Amisulpride/
23 (Analeptics or (Analeptic adj agent$) or (Analeptic adjdrug$)).tw,kf. 
24 Anti‐Anxiety Agents/ 
25 (anxiolytic$ orantianxiety agent$ or antianxiety drug$ or anti anxiety agent$ or antianxiety drug$).tw,kf.
26 exp Anticonvulsants/ 
27(Anticonvulsant$ or anti‐convulsant$).mp. 
28 (antiepileptic$ oranti‐epileptic$).mp. 
29 exp Antidepressive Agents/ 
30(antidepress$ or anti‐depress$).mp.
31 exp Antipsychotic Agents/
32 (antipsychotic$ or anti‐psychotic$).mp. 
33 expAntihypertensive Agents/ 
34 exp Antiparkinson Agents/ 
35(antiparkinson or anti‐parkinson).mp.
36 Adrenergic Uptake Inhibitors/
37 Atomoxetine Hydrochloride/ 
38 Bromocriptine/
39Buspirone/ 
40 Central Nervous System Stimulants/ 
41 CNSStimulant$.tw,kf.
42 Cholinesterase Inhibitors/
43Cholinesterase Inhibitor$.tw,kf. 
44 citalopram/ 
45Clomipramine/
46 Clonidine/ 
47 Fluoxetine/
48Fluvoxamine/
49 guanfacine/ 
50 Haloperidol/ 
51Imipramine/ 
52 Levetiracetam/ (2193)
53 LurasidoneHydrochloride/ 
54 memantine/ 
55 methylphenidate/ ordexmethylphenidate hydrochloride/
56 Milnacipran/ 
57 moodstabili#er$.mp. 
58 (neurohormone$ or neuro hormone$).tw,kf.
59(NMDA adj1 (antagonist$ or receptor$)).tw,kf.
60 Nortriptyline/
61 oxytocin/ 
62 Olanzapine/ 
63 Paliperidone Palmitate/
64 Paroxetine/ 
65 Quetiapine Fumarate/ 
66 Risperidone/
67 Rivastigmine/
68 Secretin/
69 "Serotonin andNoradrenaline Reuptake Inhibitors"/ 
70 Serotonin Uptake Inhibitors/
71 ((Serotonin adj3 Uptake Inhibitor$) or (Serotonin adj3 reuptakeInhibitor$) or (Serotonin adj3 re‐uptake Inhibitor$)).tw,kf. 
72 (SSRIor SSRIs).tw,kf. 
73 Sertraline/ 
74 Tetracyclic$.tw,kf.
75 Topiramate/ 
76 Tricyclic$.tw,kf.
77 VenlafaxineHydrochloride/ 
78 Valproic Acid/ 
79 (amantadine or amisulprideor aripiprazole or atomoxetine or bromocriptine or buspirone or Centedrin orConcerta or Daytrana or citalopram or clomipramine or clozapine ordivalproex or donepezil or Equasym or escitalopram or fluoxetine orfluvoxamine or gabapentin or guanfacine or Haloperidol or imipramine oriamotrigine or lamotrigine or levetiracetam or lurasidone or memantine orMetadate or Methylin or Methylphenidat$ or milnacipran or mirtazapine ornortriptyline or olanzapine or oxytocin or paliperidone or paroxetine orPhenidylate or quetiapine or risperidone or Ritalin$ or rivastigmine orsecretin or Sertraline or Tianeptine or Topiramate or Tsentedrin orvalproate or Venlafaxine or Ziprasidone).mp. 
80 or/13‐79 
81 12and 80 
82 randomized controlled trial.pt. 
83 controlledclinical trial.pt. 
84 randomi#ed.ab. 
85 placebo$.ab. 
86drug therapy.fs. 
87 randomly.ab. 
88 trial.ab.
89groups.ab.
90 or/82‐89 
91 exp animals/ not humans.sh. 
9290 not 91
93 81 and 92

MEDLINE In‐Process and Other Non‐Indexed Citations

1 pervasive development$ disorder$.tw,kf. 
2 DevelopmentalDisabilit$.tw,kf. 
3 neurodevelopmental disorder$.tw,kf. 
4(pervasive adj3 child$).tw,kf. 
5 (PDD or PDDs or PDD‐NOS or ASD orASDs).tw,kf.
6 autis$.tw,kf. 
7 asperger$.tw,kf.
8kanner$.tw,kf. 
9 childhood schizophrenia.tw,kf. 
10Rett$.tw,kf. 
11 or/1‐10 
12 ((pharma$ or drug) adj1(intervention$ or therap$ or treat$)).tw,kf.
13 pharmacotherap$.tw,kf.
14 (psychopharmacol$ or psycho‐pharmacol$).tw,kf. 
15 (offlabel or "off‐label").tw,kf. 
16 (novel adj1 (drug$ or medication$ orpharma$ or treatment$)).tw,kf. 
17 (acetylcholinesterase oracetyl‐cholinesterase).tw,kf. 
18 (Analeptics or (Analeptic adjagent$) or (Analeptic adj drug$)).tw,kf. 
19 (anxiolytic$ orantianxiety agent$ or antianxiety drug$ or anti anxiety agent$ or antianxiety drug$).tw,kf. 
20 (Anticonvulsant$ or anti‐convulsant$).tw,kf.
21 (antiepileptic$ or anti‐epileptic$).tw,kf.
22 (antidepress$or anti‐depress$).tw,kf. 
23 (antipsychotic$ oranti‐psychotic$).tw,kf.
24 (antiparkinson or anti‐parkinson).tw,kf.
25 CNS Stimulant$.tw,kf. 
26 central nervous systemstimulant$.tw,kf. 
27 Cholinesterase Inhibitor$.tw,kf. 
28 moodstabili#er$.tw,kf. 
29 (neurohormone$ or neuro hormone$).tw,kf.
30 (NMDA adj1 (antagonist$ or receptor$)).tw,kf. 
31((Serotonin adj3 Uptake Inhibitor$) or (Serotonin adj3 reuptake Inhibitor$)or (Serotonin adj3 re‐uptake Inhibitor$)).tw,kf. 
32 (SSRI orSSRIs).tw,kf. 
33 Tricyclic$.tw,kf. 
34 (amantadine oramisulpride or aripiprazole or atomoxetine or bromocriptine or buspirone orCentedrin or Concerta or Daytrana or citalopram or clomipramine or clozapineor divalproex or donepezil or Equasym or escitalopram or fluoxetine orfluvoxamine or gabapentin or guanfacine or Haloperidol or imipramine oriamotrigine or lamotrigine or levetiracetam or lurasidone or memantine orMetadate or Methylin or Methylphenidat$ or milnacipran or mirtazapine ornortriptyline or olanzapine or oxytocin or paliperidone or paroxetine orPhenidylate or quetiapine or risperidone or Ritalin$ or rivastigmine orsecretin or Sertraline or Tianeptine or Topiramate or Tsentedrin orvalproate or Venlafaxine or Ziprasidone).tw,kf. 
35 or/12‐34 
3611 and 35 
37 (random$ or trial$ or control$ or group$ or placebo$ orblind$ or prospectiv$ or longitudinal$ or meta‐analys$ or systematicreview$).tw. 
38 36 and 37

MEDLINE EPub Ahead of Print

1 pervasive development$ disorder$.tw,kf. 
2 DevelopmentalDisabilit$.tw,kf. 
3 neurodevelopmental disorder$.tw,kf. 
4(pervasive adj3 child$).tw,kf. 
5 (PDD or PDDs or PDD‐NOS or ASD orASDs).tw,kf.
6 autis$.tw,kf. 
7 asperger$.tw,kf.
8kanner$.tw,kf. 
9 childhood schizophrenia.tw,kf. 
10Rett$.tw,kf. 
11 or/1‐10 
12 ((pharma$ or drug) adj1(intervention$ or therap$ or treat$)).tw,kf.
13 pharmacotherap$.tw,kf.
14 (psychopharmacol$ or psycho‐pharmacol$).tw,kf. 
15 (offlabel or "off‐label").tw,kf. 
16 (novel adj1 (drug$ or medication$ orpharma$ or treatment$)).tw,kf. 
17 (acetylcholinesterase oracetyl‐cholinesterase).tw,kf. 
18 (Analeptics or (Analeptic adjagent$) or (Analeptic adj drug$)).tw,kf. 
19 (anxiolytic$ orantianxiety agent$ or antianxiety drug$ or anti anxiety agent$ or antianxiety drug$).tw,kf. 
20 (Anticonvulsant$ or anti‐convulsant$).tw,kf.
21 (antiepileptic$ or anti‐epileptic$).tw,kf.
22 (antidepress$or anti‐depress$).tw,kf. 
23 (antipsychotic$ oranti‐psychotic$).tw,kf.
24 (antiparkinson or anti‐parkinson).tw,kf.
25 CNS Stimulant$.tw,kf. 
26 central nervous systemstimulant$.tw,kf. 
27 Cholinesterase Inhibitor$.tw,kf. 
28 moodstabili#er$.tw,kf. 
29 (neurohormone$ or neuro hormone$).tw,kf.
30 (NMDA adj1 (antagonist$ or receptor$)).tw,kf. 
31((Serotonin adj3 Uptake Inhibitor$) or (Serotonin adj3 reuptake Inhibitor$)or (Serotonin adj3 re‐uptake Inhibitor$)).tw,kf. 
32 (SSRI orSSRIs).tw,kf. 
33 Tricyclic$.tw,kf. 
34 (amantadine oramisulpride or aripiprazole or atomoxetine or bromocriptine or buspirone orCentedrin or Concerta or Daytrana or citalopram or clomipramine or clozapineor divalproex or donepezil or Equasym or escitalopram or fluoxetine orfluvoxamine or gabapentin or guanfacine or Haloperidol or imipramine oriamotrigine or lamotrigine or levetiracetam or lurasidone or memantine orMetadate or Methylin or Methylphenidat$ or milnacipran or mirtazapine ornortriptyline or olanzapine or oxytocin or paliperidone or paroxetine orPhenidylate or quetiapine or risperidone or Ritalin$ or rivastigmine orsecretin or Sertraline or Tianeptine or Topiramate or Tsentedrin orvalproate or Venlafaxine or Ziprasidone).tw,kf. 
35 or/12‐34 
3611 and 35 
37 (random$ or trial$ or control$ or group$ or placebo$ orblind$ or prospectiv$ or longitudinal$ or meta‐analys$ or systematicreview$).tw. 
38 36 and 37

Embase Ovid

1 exp autism/ 
2 developmental disorder/ 
3 pervasivedevelopment$ disorder$.tw. 
4 (PDD or PDDs or ASD or ASDs).tw.
5 autis$.tw. 
6 asperger$.tw.
7 kanner$.tw.
8childhood schizophreni$.tw. 
9 Rett$.tw. 
10 (pervasive adj3child$).tw. 
11 or/1‐10 
12 drug therapy/
13 ((pharma$ ordrug) adj1 (intervention$ or therap$ or treat$)).tw,kw. 
14pharmacotherap$.tw,kw.
15 psychopharmacology/ 
16(psychopharmacol$ or psycho‐pharmacol$).tw,kw. 
17 "off label druguse"/ 
18 (off label or "off‐label").tw,kw. 
19 (novel adj1(drug$ or medication$ or pharma$ or treatment$)).tw,kw. 
20(acetylcholinesterase or acetyl‐cholinesterase).mp. 
21amisulpride/
22 central stimulant agent/
23 (Analeptics or(Analeptic adj agent$) or (Analeptic adj drug$)).tw,kw. 
24 anxiolyticagent/ 
25 (anxiolytic$ or antianxiety agent$ or antianxiety drug$ oranti anxiety agent$ or anti anxiety drug$).tw,kw. 
26 anticonvulsiveagent/ 
27 (Anticonvulsant$ or anti‐convulsant$).mp.
28(antiepileptic$ or anti‐epileptic$).mp.
29 exp antidepressant agent/
30 (antidepress$ or anti‐depress$).mp. 
31 (antipsychotic$ oranti‐psychotic$).mp.
32 exp antihypertensive agent/ 
33 expantiparkinson agent/
34 (antiparkinson or anti‐parkinson).mp.
35adrenergic receptor affecting agent/ (
36 atomoxetine/ 
37bromocriptine/ 
38 buspirone/ 
39 central stimulant agent/
40 ((CNS or central nervous system) adj Stimulant$).tw,kw. 
41cholinesterase inhibitor/
42 Cholinesterase Inhibitor$.tw,kw.
43 citalopram/ 
44 clomipramine/ 
45 clonidine/ 
46fluoxetine/
47 fluvoxamine/ 
48 fluvoxamine maleate/ 
49guanfacine/ 
50 Haloperidol/ 
51 imipramine/ 
52levetiracetam/ 
53 lurasidone/
54 memantine/
55methylphenidate/
56 milnacipran/ 
57 mood stabilizer/ 
58mood stabili#er$.tw,kw.
59 neurohormone/
60 (neurohormone$ orneuro hormone$).tw,kw.
61 (NMDA adj1 (antagonist$ orreceptor$)).tw,kw.
62 nortriptyline/
63 neuroleptic agent/
64 oxytocin/ 
65 Olanzapine/ 
66 paliperidone/ 
67paroxetine/
68 quetiapine/
69 risperidone/ 
70rivastigmine/ 
71 secretin/
72 serotonin noradrenalin reuptakeinhibitor/
73 serotonin uptake inhibitor/ 
74 ((Serotonin adj3Uptake Inhibitor$) or (Serotonin adj3 reuptake Inhibitor$) or (Serotoninadj3 re‐uptake Inhibitor$)).tw,kw. 
75 (SSRI or SSRIs).tw,kw.
76 sertraline/ 
77 Tetracyclic$.tw,kw.
78 topiramate/
79 Tricyclic$.tw,kw. 
80 venlafaxine/ 
81 valproicacid/
82 (amantadine or amisulpride or aripiprazole or atomoxetine orbromocriptine or buspirone or Centedrin or Concerta or Daytrana orcitalopram or clomipramine or clozapine or divalproex or donepezil orEquasym or escitalopram or fluoxetine or fluvoxamine or gabapentin orguanfacine or Haloperidol or imipramine or iamotrigine or lamotrigine orlevetiracetam or lurasidone or memantine or Metadate or Methylin orMethylphenidat$ or milnacipran or mirtazapine or nortriptyline or olanzapineor oxytocin or paliperidone or paroxetine or Phenidylate or quetiapine orrisperidone or Ritalin$ or rivastigmine or secretin or Sertraline orTianeptine or Topiramate or Tsentedrin or valproate or Venlafaxine orZiprasidone).mp. 
83 or/12‐82 
84 11 and 83 
85 Randomizedcontrolled trial/
86 Controlled clinical study/ 
87random$.ti,ab. 
88 randomization/ 
89 intermethod comparison/
90 placebo.ti,ab. 
91 (compare or compared orcomparison).ti.
92 ((evaluated or evaluate or evaluating or assessedor assess) and (compare or compared or comparing or comparison)).ab.
93 (open adj label).ti,ab.
94 ((double or single or doubly orsingly) adj (blind or blinded or blindly)).ti,ab.
95 double blindprocedure/ 
96 parallel group$1.ti,ab. 
97 (crossover or crossover).ti,ab.
98 ((assign$ or match or matched or allocation) adj5(alternate or group$1 or intervention$1 or patient$1 or subject$1 orparticipant$1)).ti,ab. 
99 (assigned or allocated).ti,ab.
100(controlled adj7 (study or design or trial)).ti,ab. 
101 (volunteer orvolunteers).ti,ab. 
102 human experiment/ 
103trial.ti.
104 or/85‐103
105 (random$ adj sampl$ adj7 ("crosssection$" or questionnaire$1 or survey$ or database$1)).ti,ab. not(comparative study/ or controlled study/ or randomi?ed controlled.ti,ab. orrandomly assigned.ti,ab.) 
106 Cross‐sectional study/ not (randomizedcontrolled trial/ or controlled clinical study/ or controlled study/ orrandomi?ed controlled.ti,ab. or control group$1.ti,ab.) 
107 (((caseadj control$) and random$) not randomi?ed controlled).ti,ab. 
108(Systematic review not (trial or study)).ti. 
109 (nonrandom$ notrandom$).ti,ab. 
110 "Random field$".ti,ab.
111 (random clusteradj3 sampl$).ti,ab.
112 (review.ab. and review.pt.) not trial.ti.
113 "we searched".ab. and (review.ti. or review.pt.) 
114"update review".ab. 
115 (databases adj4 searched).ab. 
116 (rator rats or mouse or mice or swine or porcine or murine or sheep or lambs orpigs or piglets or rabbit or rabbits or cat or cats or dog or dogs or cattleor bovine or monkey or monkeys or trout or marmoset$1).ti. and animalexperiment/ 
117 Animal experiment/ not (human experiment/ or human/)
118 or/105‐117 
119 104 not 118 
120 84 and 119

CINAHL EBSCOhost

S1 (MH "Child Development Disorders, Pervasive+") 
S2 (MH "RettSyndrome") 
S3 (MH "Developmental Disabilities") 
S4 (MH "MentalDisorders Diagnosed in Childhood") 
S5 TI(autis* or asperger* orkanner* or "childhood schizophrenia" or Rett* or "pervasive development*disorder*" or PDD or PDDs or PDD‐NOS or ASD or ASDs) OR AB(autis* orasperger* or kanner* or "childhood schizophrenia" or Rett* or "pervasivedevelopment* disorder*" or PDD or PDDs or PDD‐NOS or ASD or ASDs) 
S6S1 OR S2 OR S3 OR S4 OR S5 
S7 (MH "Drug Therapy") 
S8TI((pharma* or drug) N1 (intervention* or therap* or treat*)) OR AB((pharma*or drug) N1 (intervention* or therap* or treat*))
S9TI(pharmacotherap* OR psychopharmacol* or psycho‐pharmacol*) ORAB(pharmacotherap* OR psychopharmacol* or psycho‐pharmacol*) 
S10 (MH"Psychopharmacology") 
S11 (MH "Drugs, Off‐Label") 
S12 TI("offlabel" or (novel N1 (drug* or medication* or pharma* or treatment*))) ORAB("off label" or (novel N1 (drug* or medication* or pharma* ortreatment*))) 
S13 TI(acetylcholinesterase or acetyl‐cholinesterase)OR AB(acetylcholinesterase or acetyl‐cholinesterase) 
S14 (MH"Antianxiety Agents") OR (MH "Anticonvulsants") OR (MH "AntidepressiveAgents+") OR (MH "Antipsychotic Agents+") OR (MH "Central Nervous SystemStimulants+") 
S15 (MH "Antihypertensive Agents+") 
S16 (MH"Antiparkinson Agents") 
S17 (MH "Adrenergic Uptake Inhibitors") OR(MH "Serotonin Uptake Inhibitors") OR(MH "Cholinesterase Inhibitors")
S18 (MH "Atomoxetine") 
S19 (MH "Bromocriptine") 
S20 (MH"Buspirone") 
S21 (MH "Citalopram") 
S22 (MH "Clomipramine")
S23 (MH "Clonidine") 
S24 (MH "Fluoxetine") 
S25 (MH"Fluvoxamine Maleate") 
S26 (MH "Haloperidol") 
S27 (MH"Imipramine") 
S28 (MH "Memantine") 
S29 (MH "Methylphenidate")
S30 (MH "Milnacipran Hydrochloride") 
S31 (MH "Nortriptyline")
S32 (MH "Oxytocin") 
S33 (MH "Olanzapine") 
S34 (MH"Paliperidone") 
S35 (MH "Paroxetine") 
S36 (MH "Quetiapine")
S37 (MH "Risperidone") 
S38 (MH "Rivastigmine")
S39 (MH"Secretin") 
S40 (MH "Topiramate") 
S41 (MH "Venlafaxine")
S42 (MH "Valproic Acid") 
S43 (MH "Sertraline Hydrochloride")
S44 "(acetylcholinesterase or acetyl‐cholinesterase)" 
S45(Analeptics or ("Analeptic agent*") or ("Analeptic Drug*") )
S46(anxiolytic* or "antianxiety agent*" or "antianxiety drug*" or "anti anxietyagent*" or "anti anxiety drug*")
S47 (Anticonvulsant* or "anticonvulsant*") 
S48 (antiepileptic* or "anti epileptic*") 
S49(antiepileptic* or "anti epileptic*") 
S50 (antidepress* or "antidepress*") 
S51 (antipsychotic* or "anti psychotic*") 
S52(antiparkinson or "anti‐parkinson") 
S53 ("antiparkinson or"anti‐parkinson") 
S54 (CNS or "central nervous Stimulant*")
S55 "Cholinesterase Inhibitor*" 
S56 ("mood stabili*er*")
S57 neurohormone* or neuro‐hormone* 
S58 (NMDA N1 (antagonist*or receptor*)) 
S59 ((Serotonin N3 "Uptake Inhibitor*") or (SerotoninN3 "reuptake Inhibitor*") or ("Serotonin N3 "re‐uptake Inhibitor*"))
S60 (SSRI or SSRIs) 
S61 Tricyclic* 
S62 (amantadine oramisulpride or aripiprazole or atomoxetine or bromocriptine or buspirone orCentedrin or Concerta or Daytrana or citalopram or clomipramine or clozapineor divalproex or donepezil or Equasym or escitalopram or fluoxetine orfluvoxamine or gabapentin or guanfacine or Haloperidol or imipramine oriamotrigine or lamotrigine or levetiracetam or lurasidone or memantine orMetadate or Methylin or Methylphenidat* or milnacipran or mirtazapine ornortriptyline or olanzapine or oxytocin or paliperidone or paroxetine orPhenidylate or quetiapine or risperidone or Ritalin* or rivastigmine orsecretin or Sertraline or Tianeptine or Topiramate or Tsentedrin orvalproate or Venlafaxine or Ziprasidone) 
S63 S7 OR S8 OR S9 OR S10 ORS11 OR S12 OR S13 OR S14 OR S15 OR S16 OR S17 OR S18 OR S19 OR S20 OR S21 ORS22 OR S23 OR S24 OR S25 OR S26 OR S27 OR S28 OR S29 OR S30 OR S31 OR S32 ORS33 OR S34 OR S35 OR S36 OR S37 OR S38 OR S39 OR S40 OR S41 OR S42 OR S43 ORS44 OR S45 OR S46 OR S47 OR S48 OR S49 OR S50 OR S51 OR S52 OR S53 OR S54 ORS55 OR S56 OR S57 OR S58 OR S59 OR S60 OR S61 OR S62 
S64 S6 AND S63
S65 MH ("Randomized Controlled Trials") 
S66 (MH "Double‐BlindStudies") 
S67 (MH "Single‐Blind Studies") 
S68 (MH "RandomAssignment") 
S69 (MH "Pretest‐Posttest Design") 
S70 MH("Cluster Sample") 
S71 TI (randomised OR randomized) 
S72 AB(random*) 
S73 TI (trial) 
S74 (MH "Sample Size") AND AB(assigned OR allocated OR control) 
S75 MH (Placebos) 
S76 PT(Randomized Controlled Trial) 
S77 AB (control W5 group) 
S78 MH("Crossover Design") OR MH ("Comparative Studies") 
S79 AB (cluster W3RCT) 
S80 (MH "Animals+") 
S81 MH ("Animal Studies") 
S82TI (animal model*) 
S83 S80 OR S81 OR S82 
S84 MH ("Human")
S85 S83 NOT S84 
S86 S65 OR S66 OR S67 OR S68 OR S69 OR S70 ORS71 OR S72 OR S73 OR S74 OR S75 OR S76 OR S77 OR S78 OR S79 
S87 S86NOT S85 
S88 S64 AND S87

APA PsycInfo

1 exp autism spectrum disorders/ 
2 neurodevelopmental disorders/
3 Developmental disabilities/ 
4 pervasive development$disorder$.tw. 
5 (pervasive adj3 child$).tw. 
6 autis$.tw.
7 asperger$.tw.
8 (autis$ or ASD or ASDs).tw. 
9Rett$.tw. 
10 Kanner$.tw.
11 (PDD or PDDs or PDD‐NOS or ASD orASDs).tw. 
12 childhood schizophreni$.tw.
13 or/1‐12 
14Drug Therapy/ 
15 ((pharma$ or drug) adj1 (intervention$ or therap$ ortreat$)).tw. 
16 pharmacotherap$.tw. 
17psychopharmacology/
18 (psychopharmacol$ orpsycho‐pharmacol$).tw.
19 (off label or "off‐label").tw. 
20(novel adj1 (drug$ or medication$ or pharma$ or treatment$)).tw. 
21"prescribing (drugs)"/ 
22 exp Acetylcholinesterase/ or expAcetylcholine/ 
23 (acetylcholinesterase oracetyl‐cholinesterase).mp.
24 analeptic drugs/ 
25 (Analepticsor (Analeptic adj agent$) or (Analeptic adj drug$)).tw. 
26(anxiolytic$ or antianxiety agent$ or antianxiety drug$ or anti anxietyagent$ or anti anxiety drug$).tw. 
27 Tranquilizing Drugs/ orsedatives/ 
28 Anticonvulsive Drugs/ 
29 (Anticonvulsant$ oranti‐convulsant$).tw.
30 (antiepileptic$ oranti‐epileptic$).tw.
31 Antidepressant Drugs/ or tricyclicantidepressant drugs/
32 (antidepress$ or anti‐depress$).tw. 
33exp Neuroleptic Drugs/ 
34 (antipsychotic$ or anti‐psychotic$).tw.
35 antihypertensive drugs/
36 exp antihypertensive drugs/
37 exp antitremor drugs/
38 (antiparkinson oranti‐parkinson).tw. 
39 atomoxetine/ 
40 bromocriptine/
41buspirone/ 
42 Cns stimulating drugs/ 
43 ((Central NervousSystem or CNS) adj stimulant$).tw. 
44 cholinesterase inhibitors/
45 Cholinesterase Inhibitor$.tw.
46 citalopram/ 
47chlorimipramine/
48 clonidine/
49 fluoxetine/
50fluvoxamine/ 
51 haloperidol/ 
52 imipramine/
53methylphenidate/ 
54 mood stabilizers/
55 mood stabili#er$.tw.
56 (neurohormone$ or neuro hormone$).tw. 
57 (NMDA adj1(antagonist$ or receptor$)).tw. 
58 nortriptyline/ 
59 oxytocin/
60 olanzapine/ 
61 paroxetine/ 
62 quetiapine/
63risperidone/ 
64 exp Serotonin Reuptake Inhibitors/ or exp SerotoninNorepinephrine Reuptake Inhibitors/
65 neurotransmitter uptakeinhibitors/ 
66 ((Serotonin adj3 Uptake Inhibitor$) or (Serotonin adj3reuptake Inhibitor$) or (Serotonin adj3 re‐uptake Inhibitor$)).tw. 
67(SSRI or SSRIs).tw. 
68 Sertraline/
69 Tetracyclic$.tw.
70Venlafaxine/ 
71 Valproic Acid/
72 (amantadine or amisulpride oraripiprazole or atomoxetine or bromocriptine or buspirone or Centedrin orConcerta or Daytrana or citalopram or clomipramine or clozapine ordivalproex or donepezil or Equasym or escitalopram or fluoxetine orfluvoxamine or gabapentin or guanfacine or Haloperidol or imipramine oriamotrigine or lamotrigine or levetiracetam or lurasidone or memantine orMetadate or Methylin or Methylphenidat$ or milnacipran or mirtazapine ornortriptyline or olanzapine or oxytocin or paliperidone or paroxetine orPhenidylate or quetiapine or risperidone or Ritalin$ or rivastigmine orsecretin or Sertraline or Tianeptine or Topiramate or Tsentedrin orvalproate or Venlafaxine or Ziprasidone).mp. 
73 or/14‐72 
74 13and 73 
75 clinical trials/ 
76 longitudinal studies/ 
77exp program evaluation/ 
78 exp Treatment Effectiveness Evaluation/
79 random$.tw.
80 ((singl$ or doubl$ or trebl$ or tripl$) adj(blind$ or mask$)).tw. 
81 (crossover$ or "cross over$").tw. 
82trial$.tw. 
83 group$.ab. 
84 treatment effectivenessevaluation/
85 ((singl$ or doubl$ or tripl$ or trebl$) adj1 (blind$ ormask$)).tw. 
86 prospective.tw. (60764)
87factorial$.tw.
88 random$.tw. 
89 (assign$ orallocat$).ab.
90 control.ab. 
91 treatment as usual.ab.
92 placebo.ab. 
93 (crossover or cross‐over).tw.
94((effectiveness or evaluat$) adj3 (stud$ or research$)).tw. 
95or/75‐94 
96 74 and 95

ERIC EBSCOhost

S1 DE "Developmental Disabilities" 
S2 DE "Pervasive DevelopmentalDisorders" OR DE "Asperger Syndrome" OR DE "Autism" 
S3 (pervasivedevelopment* disorder* or PDD or PDDs) 
S4 (autis* or ASD or ASDs)
S5 Asperger* 
S6 Rett* 
S7 Kanner* 
S8 childhoodschizophren* 
S9 S1 OR S2 OR S3 OR S4 OR S5 OR S6 OR S7 OR S8
S10 DE "Pharmacology" 
S11 (anxiolytic* or "antianxiety agent*"or "antianxiety drug*" or "anti anxiety agent*" or "anti anxietydrug*")
S12 (Anticonvulsant* or "anti convulsant*") 
S13(antiepileptic* or "anti epileptic*") 
S14 (antidepress* or "antidepress*") 
S15 (antipsychotic* or "anti psychotic*") 
S16(antiparkinson or "anti‐parkinson") 
S17 (CNS or "central nervousStimulant*" )
S18 "Cholinesterase Inhibitor*" 
S19 ("moodstabili*er*") 
S20 neurohormone* or neuro‐hormone* 
S21 (NMDA N1(antagonist* or receptor*)) 
S22 ((Serotonin N3 "Uptake Inhibitor*")or (Serotonin N3 "reuptake Inhibitor*") or ("Serotonin N3 "re‐uptakeInhibitor*")) 
S23 (SSRI or SSRIs) 
S24 Tricyclic* 
S25(amantadine or amisulpride or aripiprazole or atomoxetine or bromocriptineor buspirone or Centedrin or Concerta or Daytrana or citalopram orclomipramine or clozapine or divalproex or donepezil or Equasym orescitalopram or fluoxetine or fluvoxamine or gabapentin or guanfacine orHaloperidol or imipramine or iamotrigine or lamotrigine or levetiracetam orlurasidone or memantine or Metadate or Methylin or Methylphenidat* ormilnacipran or mirtazapine or nortriptyline or olanzapine or oxytocin orpaliperidone or paroxetine or Phenidylate or quetiapine or risperidone orRitalin* or rivastigmine or secretin or Sertraline or Tianeptine orTopiramate or Tsentedrin or valproate or Venlafaxine or Ziprasidone)
S26 S10 OR S11 OR S12 OR S13 OR S14 OR S15 OR S16 OR S17 OR S18 ORS19 OR S20 OR S21 OR S22 OR S23 OR S24 OR S25 
S27 S9 AND S26
S28 DE "Randomized Controlled Trials" 
S29 RCT* 
S30*randomly or randomi*ed) N3 (allocated* or assign* or group* ) 
S31control group* or experimental group* 
S32 placebo* or "treatment asusual" or TAU 
S33 S28 OR S29 OR S30 OR S31 OR S32 
S34 S27 ANDS33

Epistemonikos

title:(( amantadine OR amisulpride OR aripiprazole OR atomoxetine ORbromocriptine OR buspirone OR Centedrin OR Concerta OR Daytrana ORcitalopram OR clomipramine OR clozapine OR divalproex OR donepezil OREquasym OR escitalopram OR fluoxetine OR fluvoxamine OR gabapentin ORguanfacine OR Haloperidol OR imipramine OR iamotrigine OR lamotrigine ORlevetiracetam OR lurasidone OR memantine OR Metadate OR Methylin ORMethylphenidat$ OR milnacipran OR mirtazapine OR nortriptyline OR olanzapineOR oxytocin OR paliperidone OR paroxetine OR Phenidylate OR quetiapine ORrisperidone OR Ritalin$ OR rivastigmine OR secretin OR Sertraline ORTianeptine OR Topiramate OR Tsentedrin OR valproate OR Venlafaxine ORZiprasidone)) OR abstract:(( amantadine OR amisulpride OR aripiprazole ORatomoxetine OR bromocriptine OR buspirone OR Centedrin OR Concerta ORDaytrana OR citalopram OR clomipramine OR clozapine OR divalproex ORdonepezil OR Equasym OR escitalopram OR fluoxetine OR fluvoxamine ORgabapentin OR guanfacine OR Haloperidol OR imipramine OR iamotrigine ORlamotrigine OR levetiracetam OR lurasidone OR memantine OR Metadate ORMethylin OR Methylphenidat$ OR milnacipran OR mirtazapine OR nortriptylineOR olanzapine OR oxytocin OR paliperidone OR paroxetine OR Phenidylate ORquetiapine OR risperidone OR Ritalin$ OR rivastigmine OR secretin ORSertraline OR Tianeptine OR Topiramate OR Tsentedrin OR valproate ORVenlafaxine OR Ziprasidone))) OR title:(drug* OR pharma* OR medic*) AND(title:(ASD OR autis* OR asperg* OR rett* OR pervasive OR PDD*) ORabstract:(ASD OR autis* OR asperg* OR rett* OR pervasive OR PDD*))

Science Citation Index‐ Expanded Web of Science,Clarivate

# 26 #25 AND #22 
# 25 #24 OR #23 
# 24 ab=(randomi*sed orrandomly or trial* or control* or RCT or placebo* or blind* or "treatment asusual" or TAU) 
# 23 ti=(random* or trial* or control* or RCT )
# 22 #21 AND #1 
# 21 #20 OR #19 OR #18 OR #17 OR #16 OR #15 OR#14 OR #13 OR #12 OR #11 OR #10 OR #9 OR #8 OR #7 OR #6 OR #5 OR #4 OR #3 OR#2 
# 20 ti=(amantadine or amisulpride or aripiprazole or atomoxetineor bromocriptine or buspirone or Centedrin or Concerta or Daytrana orcitalopram or clomipramine or clozapine or divalproex or donepezil orEquasym or escitalopram or fluoxetine or fluvoxamine or gabapentin orguanfacine or Haloperidol or imipramine or iamotrigine or lamotrigine orlevetiracetam or lurasidone or memantine or Metadate or Methylin orMethylphenidat* or milnacipran or mirtazapine or nortriptyline or olanzapineor oxytocin or paliperidone or paroxetine or Phenidylate or quetiapine orrisperidone or Ritalin* or rivastigmine or secretin or Sertraline orTianeptine or Topiramate or Tsentedrin or valproate or Venlafaxine orZiprasidone) OR ab=(amantadine or amisulpride or aripiprazole or atomoxetineor bromocriptine or buspirone or Centedrin or Concerta or Daytrana orcitalopram or clomipramine or clozapine or divalproex or donepezil orEquasym or escitalopram or fluoxetine or fluvoxamine or gabapentin orguanfacine or Haloperidol or imipramine or iamotrigine or lamotrigine orlevetiracetam or lurasidone or memantine or Metadate or Methylin orMethylphenidat* or milnacipran or mirtazapine or nortriptyline or olanzapineor oxytocin or paliperidone or paroxetine or Phenidylate or quetiapine orrisperidone or Ritalin* or rivastigmine or secretin or Sertraline orTianeptine or Topiramate or Tsentedrin or valproate or Venlafaxine orZiprasidone) 
# 19 ti=(Tricyclic*) or ab=(Tricyclic*) 
# 18ti=(SSRI or SSRIs) or ab=(SSRI or SSRIs) 
# 17 ti=((Serotonin Near/3"Uptake Inhibitor*") or (Serotonin Near/3 "reuptake Inhibitor*") or(Serotonin Near/3 "re‐uptake Inhibitor*") ) or ab=((Serotonin Near/3 "UptakeInhibitor*") or (Serotonin Near/3 "reuptake Inhibitor*") or (SerotoninNear/3 "re‐uptake Inhibitor*") ) 
# 16 ti=(NMDA Near/0 (antagonist* orreceptor*) ) or ab=(NMDA Near/0 (antagonist* or receptor*) ) 
# 15ti=(neurohormone* or "neuro hormone*") or ab=(neurohormone* or "neurohormone*") 
# 14 ti=("mood stabili*er*") or ab=("mood stabili*er*")
# 13 ti=("Cholinesterase Inhibitor*") or ab=("CholinesteraseInhibitor*") 
# 12 ti=("central nervous system stimulant*" or "CNSstimulant*") or ab=("central nervous system stimulant*" or "CNS stimulant*")
# 11 ti=(antiparkinson or "anti parkinson") or ab=(antiparkinson or"anti parkinson") 
# 10 ti=(antipsychotic* or "anti psychotic*") orab=(antipsychotic* or "anti psychotic*") 
# 9 ti=(antidepress* or"anti depress*") or ab=(antidepress* or "anti depress*") 
# 8ti=(Anticonvulsant* or "anti convulsant*") or ab=(Anticonvulsant* or "anticonvulsant*") 
# 7 ti=(anxiolytic* or "antianxiety agent*" or"antianxiety drug*" or "anti anxiety agent*" or "anti anxiety drug*") orab=(anxiolytic* or "antianxiety agent*" or "antianxiety drug*" or "antianxiety agent*" or "anti anxiety drug*") 
# 6 ti=(Analeptics or"Analeptic agent*" or "Analeptic drug*") or ab=(Analeptics or "Analepticagent*" or "Analeptic drug*") 
# 5 ti=(acetylcholinesterase or "acetylcholinesterase") or ab=(acetylcholinesterase or "acetyl cholinesterase")
# 4 ti=("off label" or (novel NEAR/0 (drug* or medication* or pharma*or treatment*) )) OR ab=("off label" or (novel NEAR/0 (drug* or medication*or pharma* or treatment*) )) 
# 3 TI=(pharmacotherap* orpsychopharmacol* or "psycho‐pharmacol*") or AB=(pharmacotherap* orpsychopharmacol* or "psycho‐pharmacol*") 
# 2 TI=((pharma* or drug)Near/1 (intervention* or therap* or treat*) ) or AB=((pharma* or drug)Near/1 (intervention* or therap* or treat*) ) 
# 1 ti=(autis* orasperg* or Rett* or kanner* or "childhood schizophrenia" or "pervasivedevelopment* disorder*" or PDD or PDDs or "PDD‐NOS" or ASD or ASDs) ORab=(autis* or asperg* or Rett* or kanner* or "childhood schizophrenia" or"pervasive development* disorder*" or PDD or PDDs or "PDD‐NOS" or ASD orASDs)

Conference Proceedings Citation Index (Science ), Web ofScience, Clarivate

# 26 #25 AND #22 
# 25 #24 OR #23 
# 24 ab=(randomi*sed orrandomly or trial* or control* or RCT or placebo* or blind* or "treatment asusual" or TAU) 
# 23 ti=(random* or trial* or control* or RCT )
# 22 #21 AND #1 
# 21 #20 OR #19 OR #18 OR #17 OR #16 OR #15 OR#14 OR #13 OR #12 OR #11 OR #10 OR #9 OR #8 OR #7 OR #6 OR #5 OR #4 OR #3 OR#2 
# 20 ti=(amantadine or amisulpride or aripiprazole or atomoxetineor bromocriptine or buspirone or Centedrin or Concerta or Daytrana orcitalopram or clomipramine or clozapine or divalproex or donepezil orEquasym or escitalopram or fluoxetine or fluvoxamine or gabapentin orguanfacine or Haloperidol or imipramine or iamotrigine or lamotrigine orlevetiracetam or lurasidone or memantine or Metadate or Methylin orMethylphenidat* or milnacipran or mirtazapine or nortriptyline or olanzapineor oxytocin or paliperidone or paroxetine or Phenidylate or quetiapine orrisperidone or Ritalin* or rivastigmine or secretin or Sertraline orTianeptine or Topiramate or Tsentedrin or valproate or Venlafaxine orZiprasidone) OR ab=(amantadine or amisulpride or aripiprazole or atomoxetineor bromocriptine or buspirone or Centedrin or Concerta or Daytrana orcitalopram or clomipramine or clozapine or divalproex or donepezil orEquasym or escitalopram or fluoxetine or fluvoxamine or gabapentin orguanfacine or Haloperidol or imipramine or iamotrigine or lamotrigine orlevetiracetam or lurasidone or memantine or Metadate or Methylin orMethylphenidat* or milnacipran or mirtazapine or nortriptyline or olanzapineor oxytocin or paliperidone or paroxetine or Phenidylate or quetiapine orrisperidone or Ritalin* or rivastigmine or secretin or Sertraline orTianeptine or Topiramate or Tsentedrin or valproate or Venlafaxine orZiprasidone) 
# 19 ti=(Tricyclic*) or ab=(Tricyclic*) 
# 18ti=(SSRI or SSRIs) or ab=(SSRI or SSRIs) 
# 17 ti=((Serotonin Near/3"Uptake Inhibitor*") or (Serotonin Near/3 "reuptake Inhibitor*") or(Serotonin Near/3 "re‐uptake Inhibitor*") ) or ab=((Serotonin Near/3 "UptakeInhibitor*") or (Serotonin Near/3 "reuptake Inhibitor*") or (SerotoninNear/3 "re‐uptake Inhibitor*") ) 
# 16 ti=(NMDA Near/0 (antagonist* orreceptor*) ) or ab=(NMDA Near/0 (antagonist* or receptor*) ) 
# 15ti=(neurohormone* or "neuro hormone*") or ab=(neurohormone* or "neurohormone*") 
# 14 ti=("mood stabili*er*") or ab=("mood stabili*er*")
# 13 ti=("Cholinesterase Inhibitor*") or ab=("CholinesteraseInhibitor*") 
# 12 ti=("central nervous system stimulant*" or "CNSstimulant*") or ab=("central nervous system stimulant*" or "CNS stimulant*")
# 11 ti=(antiparkinson or "anti parkinson") or ab=(antiparkinson or"anti parkinson") 
# 10 ti=(antipsychotic* or "anti psychotic*") orab=(antipsychotic* or "anti psychotic*") 
# 9 ti=(antidepress* or"anti depress*") or ab=(antidepress* or "anti depress*") 
# 8ti=(Anticonvulsant* or "anti convulsant*") or ab=(Anticonvulsant* or "anticonvulsant*") 
# 7 ti=(anxiolytic* or "antianxiety agent*" or"antianxiety drug*" or "anti anxiety agent*" or "anti anxiety drug*") orab=(anxiolytic* or "antianxiety agent*" or "antianxiety drug*" or "antianxiety agent*" or "anti anxiety drug*") 
# 6 ti=(Analeptics or"Analeptic agent*" or "Analeptic drug*") or ab=(Analeptics or "Analepticagent*" or "Analeptic drug*") 
# 5 ti=(acetylcholinesterase or "acetylcholinesterase") or ab=(acetylcholinesterase or "acetyl cholinesterase")
# 4 ti=("off label" or (novel NEAR/0 (drug* or medication* or pharma*or treatment*) )) OR ab=("off label" or (novel NEAR/0 (drug* or medication*or pharma* or treatment*) )) 
# 3 TI=(pharmacotherap* orpsychopharmacol* or "psycho‐pharmacol*") or AB=(pharmacotherap* orpsychopharmacol* or "psycho‐pharmacol*") 
# 2 TI=((pharma* or drug)Near/1 (intervention* or therap* or treat*) ) or AB=((pharma* or drug)Near/1 (intervention* or therap* or treat*) ) 
# 1 ti=(autis* orasperg* or Rett* or kanner* or "childhood schizophrenia" or "pervasivedevelopment* disorder*" or PDD or PDDs or "PDD‐NOS" or ASD or ASDs) ORab=(autis* or asperg* or Rett* or kanner* or "childhood schizophrenia" or"pervasive development* disorder*" or PDD or PDDs or "PDD‐NOS" or ASD orASDs)

Cochrane Database of Systematic Reviews

ID Search
#1 [mh "child development disorders, pervasive"]
#2 [mh^"Developmental Disabilities"]
#3 [mh ^"Neurodevelopmentaldisorders"]
#4 (pervasive NEAR/3 child*):ti,ab,kw
#5 (pervasiveNEXT development* NEXT disorder*):ti,ab,kw
#6 (PDD or PDDs or PDD NEXTNOS or ASD or ASDs):ti,ab,kw
#7 autis*:ti,ab,kw
#8asperger*:ti,ab,kw
#9 kanner*:ti,ab,kw
#10 childhood nextschizophrenia:ti,ab,kw
#11 Rett*:ti,ab,kw
#12 {OR#1‐#11}
#13 [mh ^"Drug therapy"]
#14 ((pharma* or drug) NEAR/1(intervention* or therap* or treat*)):ti,ab,kw
#15pharmacotherap*:ti,ab,kw
#16 [mh ^Psychopharmacology]
#17(psychopharmacol* or psycho next pharmacol*):ti,ab,kw
#18 [mh^"Off‐Label Use"]
#19 (off next label ):ti,ab,kw
#20 (novelNEAR/1 (drug* or medication* or pharma* or treatment*)):ti,ab,kw
#21(acetylcholinesterase or acetyl NEXT cholinesterase):ti,ab,kw
#22 [mh^Amisulpride]
#23 (Analeptics or (Analeptic near agent*) or (Analepticnear drug*)):ti,ab,kw
#24 [mh ^"Anti‐Anxiety Agents"]
#25(anxiolytic* or antianxiety NEXT agent* or antianxiety NEXT drug* or antiNEXT anxiety NEXT agent* or anti NEXT anxiety NEXT drug*):ti,ab,kw
#26[mh Anticonvulsants]
#27 (Anticonvulsant* or anti nextconvulsant*):ti,ab,kw
#28 (antiepileptic* or anti nextepileptic*):ti,ab,kw
#29 [mh "Antidepressive Agents"]
#30(antidepress* or anti NEXT depress*)
#31 [mh "AntipsychoticAgents"]
#32 (antipsychotic* or anti nextpsychotic*):ti,ab,kw
#33 [mh "Antihypertensive Agents"]
#34 [mh"Antiparkinson Agents"]
#35 (antiparkinson or anti nextparkinson):ti,ab,kw
#36 [mh ^"Adrenergic Uptake Inhibitors"]
#37[mh ^"Atomoxetine Hydrochloride"]
#38 [mh Bromocriptine]
#39 [mhBuspirone]
#40 [mh "Central Nervous System Stimulants"]
#41((CNS or central next nervous) next Stimulant*):ti,ab,kw
#42 [mh"Cholinesterase Inhibitors"]
#43 (Cholinesterase nextInhibitor*):ti,ab,kw
#44 [mh citalopram]
#45 [mhClomipramine]
#46 [mh Clonidine]
#47 [mh Fluoxetine]
#48[mh Fluvoxamine]
#49 [mh guanfacine]
#50 [mhHaloperidol]
#51 [mh Imipramine]
#52 [mhLevetiracetam]
#53 [mh "Lurasidone Hydrochloride"]
#54 [mhmemantine]
#55 [mh methylphenidate]
#56 [mhMilnacipran]
#57 (mood next stabili*er*):ti,ab,kw
#58(neurohormone* or neuro NEXT hormone*):ti,ab,kw
#59 (NMDA NEAR/1(antagonist* or receptor*)):ti,ab,kw
#60 [mh Nortriptyline]
#61[mh oxytocin]
#62 [mh Olanzapine]
#63 [mh "PaliperidonePalmitate"]
#64 [mh Paroxetine]
#65 [mh "QuetiapineFumarate"]
#66 [mh Risperidone]
#67 [mh Rivastigmine]
#68[mh Secretin]
#69 [mh "Serotonin and Noradrenaline ReuptakeInhibitors"]
#70 [mh "Serotonin Uptake Inhibitors"]
#71((Serotonin NEAR/3 Uptake NEXT Inhibitor*) or (Serotonin NEAR/3 reuptakeNEXT Inhibitor*) or (Serotonin NEAR/3 re NEXT uptake NEXTInhibitor*)):ti,ab,kw
#72 (SSRI or SSRIs):ti,ab,kw
#73 [mhSertraline]
#74 Tetracyclic*:ti,ab,kw
#75 [mhTopiramate]
#76 Tricyclic*:ti,ab,kw
#77 [mh "VenlafaxineHydrochloride"]
#78 [mh "Valproic Acid"]
#79 (amantadine oramisulpride or aripiprazole or atomoxetine or bromocriptine or buspirone orCentedrin or Concerta or Daytrana or citalopram or clomipramine or clozapineor divalproex or donepezil or Equasym or escitalopram or fluoxetine orfluvoxamine or gabapentin or guanfacine or Haloperidol or imipramine oriamotrigine or lamotrigine or levetiracetam or lurasidone or memantine orMetadate or Methylin or Methylphenidat* or milnacipran or mirtazapine ornortriptyline or olanzapine or oxytocin or paliperidone or paroxetine orPhenidylate or quetiapine or risperidone or Ritalin* or rivastigmine orsecretin or Sertraline or Tianeptine or Topiramate or Tsentedrin orvalproate or Venlafaxine or Ziprasidone):ti,ab,kw
#80 {or#13‐#79}
#81 #12 and #80 in Cochrane Reviews, Cochrane Protocols

LILACS (lilacs.bvsalud.org/en/)

(ti:((drug* OR pharma* OR medic*) AND (asd OR autis* OR asperg* OR rett* ORpervasive OR pdd*))) OR (( amantadine OR amisulpride OR aripiprazole ORatomoxetine OR bromocriptine OR buspirone OR centedrin OR concerta ORdaytrana OR citalopram OR clomipramine OR clozapine OR divalproex ORdonepezil OR equasym OR escitalopram OR fluoxetine OR fluvoxamine ORgabapentin OR guanfacine OR haloperidol OR imipramine OR iamotrigine ORlamotrigine OR levetiracetam OR lurasidone OR memantine OR metadate ORmethylin OR methylphenidat* OR milnacipran OR mirtazapine OR nortriptylineOR olanzapine OR oxytocin OR paliperidone OR paroxetine OR phenidylate ORquetiapine OR risperidone OR ritalin* OR rivastigmine OR secretin ORsertraline OR tianeptine OR topiramate OR tsentedrin OR valproate ORvenlafaxine OR ziprasidone) AND (asd OR autis* OR asperg* OR rett* ORpervasive OR pdd*)) AND ( db:("LILACS") ANDtype_of_study:("clinical_trials"))

Sociological Abstracts (Proquest)

(SU.EXACT("Medications") OR( Psychopharmacology OR Amantadine ORAnticonvulsants OR Antidepressive Agents OR Antipsychotic Agents ORAntihypertensive Agents OR Antiparkinson Agents OR Central Nervous SystemAgents OR Cholinesterase Inhibitors OR Citalopram OR Clomipramine ORClonidine OR Clozapine OR Fluoxetine OR Fluvoxamine OR Gabapentin ORGuanfacine OR Haloperidol OR Imipramine OR Memantine OR Nortriptyline ORParoxetine OR Risperidone OR Serotonin Uptake Inhibitors OR Sertraline) OR(pharmacotherap* OR Amantadine OR Aripiprazole OR Cholinesterase Inhibitor*OR Citalopram OR Citalopram OR Clomipramine OR Clonidine OR Clozapine ORDivalproex OR Donepezil OR Escitalopram OR Fluoxetine OR Fluvoxamine ORGabapentin OR Guanfacine OR Haloperidol OR Imipramine OR Lamotrigine ORMemantine OR Mirtazapine OR Nortriptyline OR Olanzapine OR Paliperidone ORParoxetine OR Quetiapine OR Risperidone OR Rivastigmine OR Serotonin ORSertraline OR Tetracyclic* OR Tianeptine OR Tricyclic* OR Venlafaxine ORZiprasidone) OR ((pharma* OR drug) NEAR/1 (intervention* OR therap* ORtreat*)) OR (psychopharmacol* OR psycho‐pharmacol*) OR (off label OR"off‐label") OR (novel NEAR/1 (drug* OR medication* OR pharma* ORtreatment*)) OR (Anticonvulsant* OR anti‐convulsant* OR antiepileptic* ORanti‐epileptic* OR antidepress* OR anti‐depress* OR antipsychotic* ORanti‐psychotic* OR antiparkinson OR anti‐parkinson OR acetylcholinesteraseOR acetyl‐cholinesterase) OR ("mood stabiliser" OR "mood stabilizer") OR(mood stabiliser) OR (mood stabilizer) OR (NMDA NEAR/1 (antagonist* ORreceptor*)) OR (NMDA NEAR/1 antagonist*) OR (SSRI OR SSRIs) ) AND((randomized controlled trial) OR (controlled clinical trial) OR (randomisedOR randomized) OR placebo* OR (drug therapy) OR ab(randomly) OR ab(trial) ORab(groups)) AND (su(child development disorders, pervasive) ORsu(Developmental Disabilities) OR (PDD OR PDDs OR PDD‐NOS OR ASD OR ASDs) OR(pervasive development* disorder*) OR (pervasive NEAR/3 child*) OR (autis*OR asperger* OR kanner* OR Rett*) OR (childhood schizophrenia))

ClinicalTrials.gov

Advanced search

53 Studies found for: Interventional Studies | Autism OR Autism SpectrumDisorder OR ASPERGER OR RETT OR PDD‐NOS OR PERVASIVE DEVELOPMENT DISORDER |amantadine OR amisulpride OR aripiprazole OR atomoxetine OR bromocriptine ORbuspirone OR Centedrin OR Concerta OR Daytrana OR citalopram OR clomipramineOR clozapine OR divalproex OR donepezil OR Equasym OR escitalopram ORfluoxetin

26 Studies found for: Interventional Studies | Autism OR Autism SpectrumDisorder OR ASPERGER OR RETT OR PDD‐NOS OR PERVASIVE DEVELOPMENT DISORDER |fluvoxamine OR gabapentin OR guanfacine OR Haloperidol OR imipramine ORiamotrigine OR lamotrigine OR levetiracetam OR lurasidone OR memantine ORMetadate OR Methylin OR Methylphenidate OR milnacipran OR mirtazapine ORnortriptyline

78 Studies found for: Interventional Studies | Autism OR Autism SpectrumDisorder OR ASPERGER OR RETT OR PDD‐NOS OR PERVASIVE DEVELOPMENT DISORDER |olanzapine OR oxytocin OR paliperidone OR paroxetine OR Phenidylate ORquetiapine OR risperidone OR Ritalin* OR rivastigmine OR secretin ORSertraline OR Tianeptine OR Topiramate OR Tsentedrin OR valproate ORVenlafaxine OR Ziprasidone

29 Studies found for: Interventional Studies | Autism OR Autism SpectrumDisorder OR ASPERGER OR RETT OR PDD‐NOS OR PERVASIVE DEVELOPMENT DISORDER |drug OR pharmacological OR medicine

WHO ICTRP

The WHO ICTRP site was affected by heavy search traffic in November 2020 dueto COVID, therefore an abbreviated form of the search was used.

BASIC SEARCH

autism AND amantadine OR autism AND amisulpride OR autism AND aripiprazole ORautism AND atomoxetine OR autism AND bromocriptine OR autism AND buspironeOR autism AND Centedrin OR autism AND Concerta OR autism AND Daytrana ORautism AND citalopram OR autism AND clomipramine OR autism AND clozapine ORautism AND divalproex OR autism AND donepezil OR autism AND Equasym ORautism AND escitalopram OR autism AND fluoxetin [49 RECORDS]

Autism AND fluvoxamine OR Autism AND gabapentin OR Autism AND guanfacine ORAutism AND Haloperidol OR Autism AND imipramine OR Autism AND iamotrigine ORAutism AND lamotrigine OR Autism AND levetiracetam OR Autism AND lurasidoneOR Autism AND memantine OR Autism AND Metadate OR Autism AND Methylin ORAutism AND Methylphenidate OR Autism AND milnacipran OR Autism ANDmirtazapine OR Autism AND nortriptyline [34 records]

Autism AND olanzapine OR Autism AND oxytocin OR Autism AND paliperidone ORAutism AND paroxetine OR Autism AND Phenidylate OR Autism AND quetiapine ORAutism AND risperidone OR Autism AND Ritalin OR Autism AND rivastigmine ORAutism AND secretin OR Autism AND Sertraline OR Autism AND Tianeptine ORAutism AND Topiramate OR Autism AND Tsentedrin OR Autism AND valproate ORAutism AND Venlafaxine OR Autism AND Ziprasidone [145 records]

Searching other resources

We contacted study authors when outcomes relevant to this review were eithernot reported fully or were reported using data not suitable for use insystematic reviews. Where contact details were no longer valid (such as anemail bouncing) we made further attempts to find up‐to‐date details of therelevant researchers. We tried to contact study authors at least twice torequest further information and noted if a reply had not been received. Werequested information regarding the following studies.

Ovid MEDLINE search strategy

1 exp child development disorders, pervasive/

2 Developmental Disabilities/

3 pervasive development$ disorder$.tw.

4 (pervasive adj3 child$).tw.

5 (PDD or PDDs or PDD‐NOS or ASD or ASDs).tw.

6 autis$.tw.

7 asperger$.tw.

8 kanner$.tw.

9 childhood schizophrenia.tw.

10 Rett$.tw.

11 or/1‐10

12 Drug Therapy/

13 ((pharma$ or drug) adj1 (intervention$ or therap$ or treat$)).tw.

14 pharmacotherap$.tw.
15 Psychopharmacology/
16(psychopharmacol$ or psycho‐pharmacol$).tw.
17 “Off‐LabelUse”/
18 (off label or “off‐label”).tw.
19 (novel adj1 (drug$ ormedication$ or pharma$ or treatment$)).tw.
20 Amantadine/
21Amantadine.mp.
22 exp Anticonvulsants/
23 (Anticonvulsant$ oranti‐convulsant$).mp.
24 (antiepileptic$ oranti‐epileptic$).mp.
25 exp Antidepressive Agents/
26(antidepress$ or anti‐depress$).mp.
27 exp AntipsychoticAgents/
28 (antipsychotic$ or anti‐psychotic$).mp.
29 expAntihypertensive Agents/
30 exp Antiparkinson Agents/
31(antiparkinson or anti‐parkinson).mp.
32 Aripiprazole.mp.
33Central Nervous System Agents/
34 Cholinesterase Inhibitors/
35Cholinesterase Inhibitor$.mp.
36 (acetylcholinesterase oracetyl‐cholinesterase).mp.
37 citalopram/
38citalopram.mp.
39 Clomipramine/
40 Clomipramine.mp.
41Clonidine/
42 Clonidine.mp.
43 Clozapine/
44Clozapine.mp.
45 divalproex.mp.
46 donepezil.mp.
47Escitalopram.mp.
48 Fluoxetine/
49 Fluoxetine.mp.
50Fluvoxamine/
51 Fluvoxamine.mp.
52 gabapentin.mp.
53guanfacine/
54 guanfacine.mp.
55 Haloperidol/
56Haloperidol.mp.
57 Imipramine/
58 Imipramine.mp.
59lamotrigine.mp.
60 memantine/
61 memantine.mp.
62Mirtazapine.mp.
63 mood stabili#er$.mp.
64 (NMDA adj1(antagonist$ or receptor$)).mp.
65 Nortriptyline/
66Nortriptyline.mp.

67 Olanzapine.mp.
68 Paliperidone.mp.
69 Paroxetine/
70Paroxetine.mp.
71 Quetiapine.mp.
72 Risperidone/
73Risperidone.mp.
74 Rivastigmine.mp.
75 exp Serotonin UptakeInhibitors/
76 (SSRI or SSRIs).tw.
77 serotonin.mp.
78Sertraline/
79 Sertraline.mp.
80 Tetracyclic$.mp.
81Tianeptine.mp.
82 Tricyclic$.mp.
83 Venlafaxine.mp.
84Ziprasidone.mp.
85 or/12‐84
86 randomized controlledtrial.pt.
87 controlled clinical trial.pt.
88randomi#ed.ab.
89 placebo$.ab.
90 drug therapy.fs.
91randomly.ab.
92 trial.ab.
93 groups.ab.
94or/86‐93
95 exp animals/ not humans.sh.
96 94 not 95
97 11and 85 and 96

Criteria for considering studies for this review

Measures of treatment effect

Unit of analysis issues

Studies with multiple intervention groups were anticipated in this area. Hadwe performed an NMA, data from any relevant multi‐arm trial could have beenretained in their original form and entered into the model accordingly.

Dealing with missing data

Had continuous data been missing, we would have imputed data using a 'lastobservation carried forward' approach. Had cases been missing from the firstoutcome measure, we would have analysed only the available data.

Assessment of heterogeneity

We would have assessed the assumption of transitivity visually, by examiningthe distribution of potential effect modifiers extracted; for example,whether antidepressants were administered the same way in studies comparingantidepressants to placebo and in those comparing antidepressants toantipsychotics.

Assessment of reporting biases

Had we conducted an NMA, and had data been sufficient, we would have used thecomparison‐adjusted funnel plot technique (Chaimani 2013).

Data synthesis

Sensitivity analysis

Although we conducted some sensitivity analyses to assess whether thefindings of this review are robust to the decisions made in the process ofobtaining them, we could not perform some sensitivity analyses.Specifically, we could not conduct the following:

• Reanalysis excluding studies according to study quality issues,including those with low sample size, high risk of bias, or highattrition and dropout rate

• Reanalysis without imputing data for the missing participants

• Reanalysis using a fixed‐effect model