In the following, we will discuss the various groups of pharmaceuticals used in children and adolescents with ASD, namely antipsychotics, antidepressants, and anticonvulsants.
Antipsychotics
Antipsychotics influence dopamine neurotransmission, act sedating in lower, antipsychotic in medium, and narcotic in high doses. First generation antipsychotics (FGA), especially haloperidol, have been shown to influence stereotypic and hyperactive behavior, to reduce temper tantrums and social isolation [
9]. FGAs should no longer be used because of an inappropriate risk–benefit ratio related to cognitive as well as early and late (e.g., dyskinetic) side effects. As an alternative, second generation antipsychotics (SGAs), especially risperidone, aripiprazole, and quetiapine, are substances of choice for treating aggression, self-injuring behavior, temper tantrums, withdrawal, tics, and rituals.
This is also true for the SGA clozapine because of its dangerous hematologic side effects [
152]. As an alternative, SGAs, especially risperidone, aripiprazole, and quetiapine, are substances of choice for treating aggression, self injuring behavior, temper tantrums, withdrawal, tics and rituals [
35,
43,
62,
68,
103,
122,
153,
170,
221,
231,
241,
249,
262,
272,
290,
295,
319]. Other SGAs (such as asenapine and iloperidone) may also be used off-label but do not offer advantages [
326]. Positive effects should be balanced against (metabolic, endocrine, neurologic, and cardiac) side effects [
61,
273]. Therefore, mainly low-dose application should be tried. Recommended dosages and specific features are listed in Table
4. Adding topiramate to risperidone therapy was more effective on overall behavior when compared to risperidone monotherapy [
257]. A potential adverse effect of topiramate on language development [
227] has, nevertheless, to be considered.
Table 3
ASD Symptoms, comorbid disorders and (off-label) pharmacotherapy
Behavioral problems, restlessness, temper tantrums, self-injuring behavior | Antipsychotics, (anticonvulsants) |
Social problems | Oxytocin, D‑cycloserin, memantine (experimental) |
Sleeping problems | Melatonin, antipsychotics, antihistaminics |
ADHD | Atomoxetin, methylphenidate, amphetamines, (guanfacine ER) |
Tics | Antipsychotics, (\(\alpha_{2}\) sympathomimetics, SSRIs) |
Depression | SSRIs, SNRIs, (+ antipsychotics) |
Bipolar disorder | Antipsychotics, (lithium) |
Anxiety & OCD | SSRIs (higher dosage needed), pregabaline |
Seizures | Valproic acid, levetiracetam, lamotrigine (and others) |
Psychosis | Antipsychotics |
GI problems | Diet? probiotics? |
Table 4
Selected antipsychotics used in children and adolescents with ASD
Risperidone | 22 h\({}^{\text{c}}\) | 0.005–0.02\({}^{\text{d}}\) also available as syrup | Standard therapy\({}^{\text{e}}\) | |
Aripiprazole | 60–80 h | 0.05–0.1\({}^{\text{f}}\) | Standard therapy\({}^{\text{g}}\) | |
Olanzapine | 30–60 h | 0.1 | SE: sedation, metabolic | |
Paliperidone | | 0.5–2 | No advantage over risperidone | |
Quetiapine | 7 h | 0.5–4 | Also acts against GAD\({}^{\text{h}}\) | |
Ziprasidone | 6 h | 0.02–0.4 | Cardiac SE (QTc \(\uparrow\)) | |
Pimozide | 55 h | 0.02–0.08 | FGA, therapy resistant tics | |
Antidepressants
In normally developing children, selective serotonin antagonists (SSRIs) are effective against depressive symptoms with substance-related differences in effectivity and side effects. SSRIs also act against anxiety disorders in lower dosages and against OCD in higher dosages, compared to the treatment of depression. In children with ASD, SSRIs are widely prescribed, but their therapeutic effect is less evident [
319]. Other AD agents, such as MAOIs, mirtazapine, hypericum, etc., also seem to produce only little effect, possibly because of elevated peripheral serotonin blood levels in a number of children and adolescents with ASD [
100,
232,
309,
319].
A few studies suggest improvements of repetitive and stereotypic behavior with AD therapy in children with ASD [
221], although this was not reported by King et al. [
168] or Williams et al. [
319]. Side effects of SSRIs usually are mild but may be exaggerated in children with ASD, especially when children are restless and agitated [
173]. Bupropion, a NDRI
6 acts like a stimulant, may create dependence, and should not be used in adolescents. Mirtazapine [
243], a tricyclic AD, has modest antidepressant effects and further acts as a sedative and hypnotic agent by stimulating H1 receptors but is slowly eliminated (
\(t\) \(1/2\) 37 h), strongly increases appetite, and leads to significant weight gain [
143]. Studies in autistic children are scarce (e.g., [
243]), and long-term studies are not available. Mirtazapine, therefore, should not be used or only used for a limited period and in low doses. Clomipramine and tricyclic antidepressants should only be used with care because of their severe side effects, and duloxetine and pregabaline have not been systematically studied in children and adolescents with ASD.
In summary, although AD medication, especially SSRIs, is widely prescribed in children and adolescents, its effectiveness is limited to not evident in children with ASD, and side effects may be more exaggerated in these patients. Therefore, the use of ADs in ASD can generally not be recommended. Because of their widespread use, pharmacologic data on AD medication are nevertheless summarized in Table
5.
Table 5
Selected antidepressants used in children and adolescents with ASD to treat depression, anxiety, and OCD
Fluoxetine | 1–6 d | 0.4–0.8 | SE: sleep & eating problems | |
Paroxetine | 12–22 h | 0.4 | Also effective against anxiety disord. and drug treatment | |
Sertraline | 23–26 h | 1 | Well tolerated | |
Agomelatin | 2.3 h | 0.5–1 | MT1 & \(\beta 2\) agonist, no systematic studies in adolescents | |
Duloxetin | 8–17 h | 0.4–1.2 | SNRI | |
Pregabalin | 6 h | 3–6–10 | GABA analogon, pain killer, anticonvulsant, anxiolytic | No studies in ASD patients |
Anticonvulsants
Anticonvulsants may be used to treat epilepsies, bipolar disorders, and externalizing behavioral problems
7. Anticonvulsant treatment of children with ASD [
83,
133,
261], like in other patients with convulsions, depends on the type of convulsions and should always be combined with psychosocial support [
261].
The most commonly used pharmacotherapeutics are valproic acid, lamotrigine, levetiracetam, and ethosuximide [
96], cf. Table
6. In select syndromes such as Landau–Kleffner syndrome or ESES
8, corticosteroids, ACTH, or immunoglobulin therapy may be considered [
303]. Additional nonpharmacological therapeutic options for therapy-resistant epilepsies include vagus nerve stimulation [
184], ketogenic diet, and neurosurgical interventions [
114]. It is not clear whether an interictal epileptiform EEG may be a cofactor contributing to neurologic deterioration or progressing developmental retardation [
310]. Pharmacologic treatment should always be considered if symptoms get worse.
Table 6
Anticonvulsants selected
Ethosuximide | 53 | 10–20–40 | Absences, well tolerated | |
| | | No effect on behavior, additive to VPS | |
Valproic acid | 12–16 | 10–15–30 | Enhances GABA-ergic inhibition | |
| | | Cortical hyperconnectivity, increases risk | |
| | | Of ASD and malformation when | |
| | | Administered during pregnancy | |
Lamotrigine | 25–50 | 0.5–4 | Against gen. and PE, well tolerated | |
| | | Against BSD, no effect on behavior | |
Levetiracetam | 7 | 20–40–60 | Against generalized and PE, SE tiredness | |
| | | No effect on behavior | |
Clobazam | 18 | 0.2–0.8 | Add-on against prim. generalized and PE | |
Clonazepam | 18–50 | 0.01–0.4 | Against myoclonus epilepsy, SE: dizziness, ataxia | |
Gabapentin | | 10–40 | Add-on against PE and sec. generalized | |
| | | Epilepsy, SE tiredness, DRESS\({}^{\text{c}}\) | |
Sultiame | 24 | 5–6 | SE: ataxia, paresthesia, anorexia | |
Topiramate | 19–25 | 1–\(4/2\) | Against PE and generalized epilepsy, | |
| | | LGS\({}^{\text{d}}\), SE tiredness | |
| | | Weight loss, cognitive | |
| | | impairment | |
Vigabatrin | 5–8 | 20–\(60/2\) | | |
Other Substances, Supplementary and Alternative Therapies
Among the “newer” pharmacologic concepts (such as IGF‑1, memantine, D‑cycloserine, arbaclofen, and oxytocin [
240,
300]), only three show promise for the future: oxytocin with the objective to improve sociogenic behavior, beta blockers to reduce stress, and the glutamate antagonist, 2‑methyl-6-(phenylethynyl)pyridine (MPEP), to reduce stereotypic behavior [
94]. For the latter substance, it is feared that sociogenic behavior may deteriorate during treatment [
297].
In the short term, intranasal oxytocin enhances motivation and attention to social stimuli, improves social initiative, understanding, learning [
8,
22,
176], and better recognition of emotions [
111]. Unfortunately, these improvements were not substantiated in long-term trials [
7,
112,
313,
321,
322]. A meta-analysis [
248] reported medium-effect sizes for prolonged oxytocin therapy in small samples. Reasons for the variation in oxytocin response include time dependency of the oxytocin response [
230], single nucleotide polymorphisms of the oxytocin receptor [
148], and lasting effects of postnatal stimulation of the oxytocin system [
300]. When studying oxytocin effects patients and targets must be carefully selected. Therefore, the clinical usefulness of oxytocin is still a matter of debate [
228,
306]. Melanocortin, stimulating oxytocin release, could be a useful alternative [
215], but large clinical trials are lacking. Still, a special edition of “Brain Research”
15 provides a comprehensive overview about the state of research.
There is only limited evidence for using beta blockers for reducing stress-related autoaggressive behavior [
312] or memantine for improving language and memory functions [
233]. Defects of GABA-A receptors, leading to deficient synaptogenesis, have been demonstrated in fragile X syndrome, a pervasive developmental disorder with known genetic defect
16. Ganaxolone, a strong GABA-A agonist, was used in a controlled clinical study [
29,
188] and was found to be safe but only effective in a subgroup of patients with fragile X syndrome, high levels of anxiety, and low intellectual capacity.
Medical cannabis, especially for ADHD, tics, sleep problems, behavioral problems, and anxiety [
2,
134,
247], may improve symptoms but does not lead to remission. Treatment evidence at present is limited to anecdotical reports and a few small studies; three further studies are to be expected. Treatment options should, therefore, be restricted to single patients in whom standard treatment did not improve severe symptoms.
Various behavioral and functional therapies, such as structured behavioral therapies [
178,
254,
299], communication and social skills training [
177,
213], occupational therapy [
49,
194], mindfulness [
259], play teaching [
162], music [
217,
289], and speech therapy, have been shown to have beneficial effects in improving development, behavior, speech, social functioning, and quality of life [
146,
191,
192,
220,
221,
275]. Physical exercise is an effective treatment option, especially in children with dual disorder, ASD and ADHD [
128,
286,
302].
Alternative, “natural” treatments seem less invasive, safer (there are no reports on dangerous action), more intuitive to understand, and easier to procure. Parents are concerned with the safety or side effects (listed in the package leaflet) of medication or are disappointed because conventional medication did not change the core symptoms of ASD [
120]. Therefore, alternative therapies are very popular [
186,
191,
316]; a third of the parents of children with ASD have tried “alternative”, “integrative”, or “complementary”
17 therapies [
185,
186,
191]. A higher educational level of the mothers predicted the use of alternative therapies [
120]. Half of the families use alternative therapies, although they do not rate them as useful.
Most of these therapies are used as an adjunct to conventional therapy. Biologically based therapies (such as diet[
239,
293], vitamins and minerals, food supplements such as omega‑3 fatty acids [
150], herbal remedies, secretin), and mind–body interventions (such as prayer, shamanism, biofeedback, meditation, and relaxation) are more often perceived efficacious than body-based methods (such as sensory integration therapy [
325], massage, craniosacral therapy, neurofeedback, and special exercises) or energy therapies (healing touch, energy transfer) [
120]. Technology based interventions seem promising because of the attention sustaining potential, but, at present, evidence of the success of such approaches is poor [
172,
250]. Examples are interventions for acquiring language skills [
226], for differentiating facial expressions [
19], treating food selectivity [
20], or anxiety or stress management [
37].
A number of physicians encourage multivitamins (49%), essential fatty acids (25%), melatonin (25%), and probiotics (19%), and discourage withholding (76%) or delaying immunizations (55%), chelation (61%), anti-infectives (57%), or secretin (43%) [
120]. It has to be stated that there is no clinical evidence for applying specific (e.g., gluten-free or pro-biotic) diets [
203], vitamins
18 [
155,
237], oligominerals, herbal medicine [
311], transfer of energy, chelates
19 [
151], or biologicals such as secretin [
180,
186]. It has been found that 10% of parents even use potentially dangerous “medication” such as “whole-brain extracts” [
185]. Medication from the Far East, such as traditional Chinese medicine or acupuncture, or osteopathy may be useful in the short-term run in improving single symptoms (restlessness, sleep disturbance); the long-term outcome is rather dubious [
45].