Psychopharmacology is the field concerned with clinical benefits of psychotropic drugs, their character-istics that predict responsiveness, side effects, toxicity, and the interactions between drug and psychological variables. In this write-up, we will discuss the journey of psychopharmacology, including hydroxyzine, and its current status.

Historical background and past knowledge: During the early to mid 20th century, society and the medical world in the West considered a model child as one who could self-regulate behavior and maintain orderly social relations. In contrast, a ‘problem child’ displayed a broad range of misbehaviors. According to severity of the problem, these children were managed with psychotherapy and medication in outpatient clinics or residential institutions (primarily meant for neurological diseases) [2]. In those days, several discoveries of psychotropic drugs for pediatric use were serendipitous. In 1937, a psychiatrist George Bradley studied the effect of Benzedrine sulphate, an amphetamine, on 30 children with behavioral problems at the Bradley Home for ‘problem children’ in America, and reported a striking improvement in 50% [3]. This paved the way for empirical experimentation with other drugs. Several studies between 1957 and 1963 reported benefits in behavior with hydroxyzine [2,4]. Stimulants started being used for ‘minimal brain dysfunction’ and antidepressants for enuresis. By the 1970’s, research methodology had evolved with placebo-controlled, double-blind studies. When scientific research demonstrated a dramatic response to stimulants in Attention Deficit Hyper-activity Disorder (ADHD), it heralded the start of the era of evidence-based use of drugs in mental health illnesses in children.

The study: This differed from previous studies by examining the effect of hydroxyzine hydrochloride on various catergories of behavior. Authors enrolled 100 children consecutively presenting to their child guidance clinic with behavioral issues, and conducted their baseline clinical and psychological assessment. Eligible participants were randomly assigned into two groups: group I received hydroxyzine (25-50 mg twice a day) for six weeks followed by a placebo for the following six weeks; and the sequence of drug administration was reversed in group II. Placebo and hydroxyzine liquid formulations were dispensed in identical bottles that were coded. Each child was followed-up weekly for parental reports about change in behavior (scored on a Likert scale renging from –1 for worse to 4 for recovery) and side effects. Blood counts, kidney function tests and urine examination were performed at baseline and on completion.

The age range of the study population was 0 to 14 years with a 2:1 boy-girl ratio. Underlying causes were organic in 39% and psychogenic in 61%. Symptoms were categorized into 10 clusters that pertained to: food intake (n=29), sleep (n=19), speech (n=10), motor behavior (n=22), body manipulation (n=8), sex behavior (n=2), emotional behavior (n=77), psychosomatic (n=40), social behavior (n=40) and hysterical behavior (n=2). In children with multiple symptoms (that ranged from 1 to 9), a mean score was computed for each child, by dividing the sum of scores by the number of behaviors.

Behavior problems in children are increasingly being recognized, including in organic disorders such as epilepsy [5] and cancer [6]. Maladaptive behaviors are behaviors severe enough to impair activities of daily living. Behaviors in typically developing children usually benefit from counseling with avoidance of inadvertent parental reinforcement. Those that satisfy the diagnostic criteria of a mental health disorder require individualized behavioral modification therapy and possibly psychoactive drugs that affect mood,　thinking, and/or behavior.

Research in psychopharmacology has made quantum leaps in the last 50 years. We know that psychoactive drugs interact with specific target sites or receptors in the central nervous system (CNS) by primarily acting on neurotransmitters. In addition. they may alter the secretion of hormones, especially from the　pituitary. These drugs may be considered for cognitive, emotional, and/or behavior symptoms when there is no response to evidence-based, non-drug therapies (provided by psychologists, social workers and counsellors), significant distress, functional impairment or risk of harm. Commonly encountered target symptoms include agitation, aggression, anxiety, depression, hyperactivity, inattention, impulsivity, mania and psychosis. The main classes of drugs in use are typical and atypical antipsychotic drugs, tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRI), stimulants and anti-anxiety drugs. The choice of drug depends on the predominant behavior and/or the underlying disorder. Stimulant medications are useful for inattention and hyperactivity; antipsychotic medications for marked irritability, and tranquilizers target aggression and mood stabilization. Long-acting stimulants are being used in ADHD, antidepressants for depression and anxiety disorders, antipsychotics for conduct disorders, and SSRIs for autism spectrum disorder, obsessive-compulsive disorder, Tourette’s disorder and motor tic disorders. To ensure safe and appropriate use, best practice principles of prescription should be followed [7]. This involves assessment, planning treatment and monitoring, obtaining assent/consent, implementing treatment, and monitoring the patient for adverse effects (especially for obesity and metabolic syndrome).

It is now known that hydroxyzine affects the CNS by reducing production of a proinflammatory cytokine, selective serotonin reuptake inhibition and increasing GABA levels [8]. This decreases anxiety and improves behavior. Current indications include pre-procedural sedation, generalized anxiety disorder, bruxism and sleep problems (especially in hepatic encephalopathy due to cirrhosis) [9,10]. With emerging evidence of its anti-inflammatory and immunomodulatory actions and lack of long-term side effects, there is a renewed interest in the treatment of neurodevelopmental disorders like Autism spectrum disorder [8]. A tale of hydroxyzine in behavioral symptoms of children that started 50 years ago has come full circle and finally made its way back.

1. Manchanda SS, Kishore B, Jain CK, Singh G, Kashyap UB. Hydroxyzine hydrochloride in the management of children with behaviour problems. Indian Pediatr. 1969;6:538-49.

2. Strohl MP. Bradley’s Benzedrine Studies on Children with Behavioral Disorders. Yale J Biol Med. 2011;84:27-33.

3. Bradley C. The behavior of children receiving Benzedrine. Am J Psychiatry. 1937;94:577-81.

4. Nathan LA, Andelman MB. The use of a tranquilizer in the management of behavior problems in a private pediatric practice. Ill Med J.1957;112:171-4.

5. Mishra OP, Upadhyay A, Prasad R, Upadhyay SK, Piplani SK. Behavioral problems in indian children with epilepsy. Indian Pediatr. 2017;54:116-20.

6. Satapathy S, Kaushal T, Bakhshi S, Chadda RK. Non-pharmacological interventions for pediatric cancer patients: A comparative review and emerging needs in India. Indian Pediatr. 2018;55:225-32.

7. American Academy of Child and Adolescent Psychiatry: Practice Parameter on the Use of Psychotropic Medication in Children and Adolescents. J Am Acad Child Adolesc Psychiatry. 2009;48:961-73.

8. Wiley TS, Raden M, Haraldsen JT. H1R antagonists for brain inflammation and anxiety: targeted treatment for autism spectrum disorders. J Pharm Drug Deliv Res. 2015;4:doi:10.4172/2325-9604.1000136.

9. Guaiana G, Barbui C, Cipriani A. Hydroxyzine for generalized anxiety disorder. Cochrane Database Syst Rev. 2010;8:CD006815.