30% of the clozapine patients responded compared to 4% of the controls, with significantly greater improvement on the Brief Psychiatric Rating Scale, Clinical Global Impression Scale, and Nurses Observation Scale for Inpatient Evaluation; this improvement included "negative" as well as positive symptom areas. Following this study, the US Food and Drug Administration (FDA) approved its use in 1990. Cautious of this risk, however, the FDA required a black box warning for specific side effects including agranulocytosis, and took the unique step of requiring patients to be registered in a formal system of tracking so that blood count levels could be evaluated on a systematic basis.In December 2002, clozapine was approved in the US for reducing the risk of suicide in people with schizophrenia or schizoaffective  judged to be at chronic risk for suicidal behavior. In 2005, the FDA approved criteria to allow reduced blood monitoring frequency. In 2015, the individual manufacturer Patient Registries were consolidated by request of the FDA into a single shared Patient Registry Called The Clozapine REMS Registry. Despite the demonstrated safety of the new FDA monitoring requirements, which have lower neutrophil levels and do not include total white cell counts, international monitoring has not been standardised. Chemistry
Clozapine is a dibenzodiazepine that is structurally very similar to loxapine (originally deemed a typical antipsychotic). It is slightly soluble in water, soluble in acetone, and highly soluble in chloroform. Its solubility in water is 0.1889 mg/L (25 °C). Its manufacturer, Novartis, claims a solubility of <0.01% in water (<100 mg/L).
Inappropriate sinus tachycardia (IST) is a rare type of cardiac arrhythmia within the category of supraventricular tachycardia (SVT). IST may be caused by the sinus node itself having an abnormal structure or function, or it may be part of a problem called dysautonomia, a disturbance and/or failure of the autonomic nervous system. Research into the mechanism and etiology (cause) of inappropriate sinus tachycardia is ongoing. IST is viewed by most to be a benign condition in the long-term. Symptoms of IST, however, may be distracting and warrant treatment. The heart is a strong muscle and typically can sustain the higher-than-normal heart rhythm, though monitoring the condition is generally recommended. The mechanism and primary etiology of inappropriate sinus tachycardia has not been fully elucidated. An autoimmune mechanism has been suggested, as several studies have detected autoantibodies that activate beta adrenoreceptors in some patients. The mechanism of the arrhythmia primarily involves the sinus node and peri-nodal tissue and does not require the AV node for maintenance. Treatments in the form of pharmacological therapy or catheter ablation are available, but the condition is currently difficult to treat successfully. Symptoms
Symptoms reported by patients vary in frequency and severity. They may include:

Frequent or sustained palpitations
Dyspnea (shortness of breath) and palpitations on exertion
Pre-syncope (feeling as if about to faint)
Fatigue
Dizziness
Exercise intolerance
Occasional paresthesia and cramping
Symptoms associated with autonomic nervous system disturbance, including gastrointestinal disturbance

Diagnosis
No formal diagnostic criteria exist.