The first extensive description of monomania, also called paranoia, was generated by the French psychiatrist Esquirol (1772–1840). He labeled this form of mental illness a partial “délire” (French for delusion), partial because, outside of the one prominent, fiercely defended, idiosyncratic, and unchangeable false belief, the patient was generally described as fully rational [1]. The term paranoia was widely used in psychiatry until the first half of the 20th century, after which it lost its status as a stand-alone diagnosis [2]. In 1987, DSM-III-R (the revision of the third U.S. diagnostic and statistical manual of mental disorders) reintroduced the concept but gave it a new name: delusional disorder [3]. Delusional disorder (DD) is considered a serious mental disorder characterized by the presence of a fixed, preoccupying, illogical belief. It is classified as a psychotic disorder, and belongs to the schizophrenia spectrum of disorders [4]. Characteristically, delusional beliefs are based on the misinterpretation of external reality, and are not, by definition, amenable to extinction by persuasion or education [5]. Delusions in DD are sometimes accompanied by affective symptoms or perception errors; however, even when present, these do not take center stage. Whenever hallucinations do occur in DD, they are congruent with the all-consuming delusional theme [5]. The current diagnostic and statistical manuals for mental disorders classify DD into seven subtypes according to the delusional content: persecutory (belief of being persecuted or conspired against), somatic (delusional parasitosis, hypochondriasis, or body dysmorphic disorder), jealous (Othello’s syndrome), grandiose (delusions of grandeur), erotomanic (de Clérambault’s syndrome), mixed (a combination of delusional themes), and unspecified (vagueness in the expression of delusional content) [5]. These subtypes are not associated in the psychiatric literature with differential responses to available treatments.

The worldwide prevalence of DD is difficult to determine accurately because many persons with DD do not consider themselves ill, and thus, never seek treatment. The condition has been considered rare, representing only 1–4% of all psychiatric admissions. It usually never comes to medical attention until middle or late adult life, although it may begin earlier ^[2][6][2,6]. There are reports of DD being consistently and cross-culturally most common in low socioeconomic groups and among new immigrants. In fact, DD occurs more frequently in immigrants than schizophrenia or affective disorder [6]; except for specific local syndromes, the sociodemographic profile is consistent across different cultures [7].

2. Treatment of Delusional Disorder Prior to the Widespread Use of Antipsychotic Medications

Before the introduction of antipsychotic medications, patients with schizophrenia and other paranoid psychoses were treated in long-term psychiatric institutions, where the emphasis was on keeping patients safe, calm, and busy. Treatment focused on safety precautions, occupational activities, and nursing care ^[8][11]. Gardening, art, music, drama, and dance therapies were some of the therapeutic modalities used in mental hospitals. Dance movement therapy was also used to improve psychological and physical well-being ^[9][12]. The mechanism by which leisure activities could improve psychotic symptoms was understudied. It was assumed that such activities were enjoyable and relaxing, encouraged in-hospital socialization, and kept patients’ minds off pathological preoccupations. Work therapy, rest cures, and a system of rewards for appropriate behavior were also offered in psychiatric asylums. Rest cures included three main elements: rest, seclusion, and good nutrition. Massage treatment was sometimes used ^[10][13]. Malaria treatment, insulin shock, lobotomy, and electroconvulsive therapy, plus three types of hydrotherapy, were the main treatments for psychosis ^[11][14]. Hydrotherapy was described as head-out hot showers, adapted cold showers, and colonic hydrotherapy. It was hypothesized that hot and cold showers reduce stress and potentially modulate neurotransmission via the mesolimbic system of the brain. Pharmaceutical compounds such as bromides, chloral hydrate, hyoscine, paraldehyde, barbiturates, and morphine were also used for sedation. Even after the introduction of chlorpromazine, paraldehyde was still in use as a comparator drug, specifically for toxic psychosis and delirium tremens ^[12][13][15,16]. Table 1 represents the main treatment options used to treat patients with psychosis, including DD, before the widespread use of chlorpromazine and related drugs. The history of antipsychotic drug development is serendipitous, with effectiveness, until the last few decades, judged solely on the basis of clinical observations. The use of phenothiazines resulted accidentally from a search for improved antihistamines ^[14][17]. Coincidentally, Paul Ehrlich had already observed, in 1891, that methylene blue, a phenothiazine derivative, functioned as an antimalarial ^[15][18]. Chlorpromazine, developed first as an antihistamine, was noted to exert calming effects without undue sedation. It was found to calm soldiers injured on the battlefield, and to act as an analgesic during surgery. This pronounced calming effect attracted the interest of psychiatrists, who thought it might work (similar to freeze wraps) by cooling the brain. The discovery of the antipsychotic effect of phenothiazines in the early 1950s was part of the “psychopharmacological revolution” ^[16][19]. Chlorpromazine was shown to be effective for psychomotor agitation in acute and chronic mania, schizophrenia, and also organic psychoses secondary to lobotomy ^[17][20]. Phenothiazines and piperazines were followed by butyrophenones ^[17][20], with haloperidol being synthesized by Paul Janssen in 1958 ^[18][21]. Haloperidol replaced chlorpromazine as the most frequently prescribed antipsychotic among the many that were soon available. As more and more chemical neurotransmitters were discovered in the brain, it became generally understood that drug effects worked through inhibiting or enhancing neurotransmission, and by exerting their effects through specialized neuronal membrane receptors. Antipsychotics were shown to be very effective in treating positive symptoms of psychosis (delusions, hallucinations, thought disorder) ^[19][22], and were used to treat these symptoms in whatever disorders they appeared. In a long-term follow-up study that investigated the clinical course and treatment response of a cohort of 72 first-admission patients diagnosed with DD ^[20][23], clinical outcomes were compared between patients admitted during the 1946–1948 period (prior to the synthesis of chlorpromazine) and those admitted during 1958–1961. Surprisingly, it was found that the two groups fared equally poorly. In other words, antipsychotic medication did not seem to improve the outcome. The dramatic improvement seen in schizophrenia was not, at that time, apparent in DD, possibly because only the most severely ill DD patients were hospitalized. Table 2 summarizes the history of antipsychotic drugs in the context of delusional disorders (DDs). Figure 1 presents the molecular structure of the main antipsychotics used to treat delusional disorder: chlorpromazine, pimozide, clozapine, aripiprazole, olanzapine and risperidone.