First-generation antipsychotics (FGAs) act primarily through competitive antagonism at dopamine D2 receptors. Their clinical diversity, ranging from haloperidol at doses of 2 to 5 mg to chlorpromazine at 400 to 800 mg, reflects differences in D2 binding affinity rather than differences in antipsychotic efficacy at equivalent receptor occupancy.
All FGAs are competitive antagonists at D2 receptors, blocking the access of endogenous dopamine (DA) to the receptor without activating it. The antipsychotic effect requires sustained striatal and mesolimbic D2 occupancy in the therapeutic range of 65 to 80%, as established by positron emission tomography (PET) imaging studies.1 Below this range, antipsychotic response is inconsistent; above 80%, extrapyramidal side effects (EPS) emerge without additional therapeutic benefit. FGAs achieve this occupancy by tight, prolonged binding at the D2 receptor, with dissociation rates that are generally slow relative to endogenous DA.
The concept of potency in the FGA class refers exclusively to the dose in milligrams required to achieve a given level of D2 receptor occupancy, not to the ceiling antipsychotic effect achievable. A high-potency agent such as haloperidol achieves 70 to 75% D2 occupancy at doses of 2 to 5 mg per day because its binding affinity for the D2 receptor is very high. A low-potency agent such as chlorpromazine requires 200 to 400 mg per day to reach equivalent occupancy because its affinity for D2 is substantially lower.2 Both agents, when titrated to equivalent D2 occupancy, produce comparable antipsychotic effect. What differs is not efficacy but the constellation of receptor interactions at the doses required, since low-potency agents must be given at doses that produce meaningful blockade at histamine H1, muscarinic M1, and alpha-1 adrenergic receptors in addition to D2, generating a very different adverse effect profile from the high-potency agents.
FGAs are classified by chemical structure into several groups: phenothiazines (further divided into aliphatic, piperidine, and piperazine subgroups), butyrophenones, thioxanthenes, and a small number of structurally distinct agents including diphenylbutylpiperidines. The structural subclassification correlates with potency and receptor selectivity. Piperazine phenothiazines (trifluoperazine, fluphenazine, perphenazine) are the highest-potency phenothiazines. Aliphatic and piperidine phenothiazines (chlorpromazine, thioridazine) are the lowest-potency and carry the highest anticholinergic and sedative burden.2 Butyrophenones (haloperidol, droperidol) are among the most D2-selective compounds in the class, with limited off-target receptor activity at clinical doses and consequently high EPS risk.
Haloperidol is the prototypical high-potency FGA and remains one of the most widely used antipsychotics globally, in part because of its proven efficacy, its long track record of safety data, and its availability in oral, intramuscular (IM), and long-acting injectable (LAI) formulations. It is a butyrophenone with very high D2 receptor affinity and limited significant activity at H1, M1, or alpha-1 receptors at standard doses, which accounts for its relatively low sedation and anticholinergic burden compared with low-potency agents.2 The oral dose range for psychosis is typically 2 to 20 mg per day, though doses above 10 mg add EPS risk without meaningful additional antipsychotic benefit in most patients. Haloperidol has a half-life of approximately 12 to 36 hours, supporting once-daily dosing in stable patients. The IM formulation (haloperidol lactate) achieves peak plasma levels within 20 to 40 minutes and is a mainstay of acute agitation management in emergency settings, typically dosed at 2 to 5 mg IM with repeat dosing as needed under observation.
Haloperidol carries the highest EPS liability of all FGAs at equivalent antipsychotic doses, a direct consequence of its D2 selectivity and slow receptor dissociation kinetics. Drug-induced parkinsonism, acute dystonia, and akathisia are common at doses above 5 mg per day in antipsychotic-naive patients. Haloperidol is also the most studied FGA for QTc prolongation, though its cardiac risk is modest compared to thioridazine; intravenous (IV) haloperidol carries a higher QTc risk than oral or IM routes and should be used with cardiac monitoring in hospitalized patients.3 Despite its adverse effect profile, haloperidol retains specific clinical advantages: it is the best-studied agent in pregnancy (with the most longitudinal neonatal outcome data), the most available agent in resource-limited settings, and the only FGA with an established evidence base for IV use in intensive care unit (ICU) delirium management.
Fluphenazine is a piperazine phenothiazine with potency comparable to haloperidol and a similar EPS burden. Its clinical role in contemporary practice is primarily as the substrate for fluphenazine decanoate, a long-acting injectable (LAI) formulation administered every 2 to 4 weeks. The oral form is used less frequently in new prescribing than haloperidol, largely because haloperidol offers more flexible dosing and broader familiarity. The oral dose range is 2 to 20 mg per day in divided doses. Fluphenazine has slightly more anticholinergic activity than haloperidol, which modestly attenuates its EPS burden in some patients, but the difference is clinically small at standard doses. Fluphenazine decanoate is the older of the two established FGA depot formulations and remains in widespread use for adherence management in patients with chronic schizophrenia, particularly in settings where the newer LAI second-generation antipsychotics (SGAs) are cost-prohibitive.2
Trifluoperazine is another piperazine phenothiazine with high D2 affinity. It was historically used for both psychosis and anxiety, though its use for anxiety disorders has been essentially replaced by benzodiazepines and modern anxiolytics. In the treatment of schizophrenia, its efficacy is comparable to other high-potency agents. The oral dose range is typically 5 to 20 mg per day. Trifluoperazine carries a high EPS burden and offers no particular pharmacological advantage over haloperidol for most indications. It is not available in an LAI formulation, which limits its utility in adherence-challenged populations.2
Perphenazine occupies a mid-to-high potency position among the phenothiazines. It requires doses of 8 to 64 mg per day divided into two to three doses and has a moderately high D2 affinity with somewhat more H1 and alpha-1 activity than haloperidol, producing a marginally more favorable EPS profile at equivalent antipsychotic doses at the cost of modestly more sedation and orthostatic effects. Perphenazine gained renewed clinical attention following the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study, in which it demonstrated comparable effectiveness to several second-generation antipsychotics (SGAs) including olanzapine, quetiapine, risperidone, and ziprasidone on the primary outcome of all-cause treatment discontinuation.4 This finding challenged the assumption that SGAs were categorically superior for chronic schizophrenia and positioned perphenazine as a cost-effective option in patients without a specific indication for an SGA.
Chlorpromazine, introduced in 1952, was the first antipsychotic drug and the agent whose clinical activity initiated the entire discipline of biological psychiatry. It is an aliphatic phenothiazine with low D2 affinity that requires doses of 200 to 1000 mg per day to achieve therapeutic D2 occupancy. At these doses, it produces substantial blockade at H1 (sedation, weight gain), M1 (dry mouth, urinary retention, constipation, cognitive impairment), and alpha-1 adrenergic (orthostatic hypotension, reflex tachycardia) receptors.2 Its EPS burden is lower than haloperidol's at equivalent antipsychotic doses, in part because its anticholinergic activity partially offsets nigrostriatal D2 blockade, and in part because lower D2 selectivity means the EPS threshold is approached more gradually.
Chlorpromazine also produces a unique adverse effect not shared to the same degree by other FGAs: photosensitivity reactions and, with long-term high-dose use, a blue-grey discoloration of sun-exposed skin and corneal-lenticular deposits detectable on slit-lamp examination.2 These pigmentary effects are dose- and duration-dependent. Chlorpromazine lowers the seizure threshold more than most other antipsychotics and carries a modest risk of cholestatic jaundice, particularly in the first weeks of treatment, reflecting hypersensitivity rather than direct hepatotoxicity. QTc prolongation is a recognized effect but less severe than with thioridazine. Despite these limitations, chlorpromazine remains in use in resource-limited global settings and for rapid sedation in acute agitation because its strong H1 and alpha-1 blocking activity produces reliable sedation at relatively low doses.
Thioridazine is a piperidine phenothiazine that shares chlorpromazine's broad receptor profile but carries a substantially more severe cardiac risk. It is a potent blocker of cardiac hERG (human ether-a-go-go-related gene) potassium channels, producing dose-dependent QTc prolongation that can progress to polymorphic ventricular tachycardia, including torsades de pointes, at doses above 300 mg per day.5 This cardiac toxicity led regulatory agencies to restrict thioridazine to use only in patients who have failed other antipsychotics, effectively limiting it to an agent of last resort in most clinical contexts. Its anticholinergic burden is the highest of the commonly used FGAs, producing a full peripheral and central anticholinergic syndrome at standard doses. Thioridazine is also associated with pigmentary retinopathy with doses exceeding 800 mg per day, a unique adverse effect within the antipsychotic class caused by melanin binding in retinal pigment epithelium and potentially leading to irreversible visual impairment.5 For these reasons, thioridazine has largely been displaced from routine practice and its prescribing requires explicit informed consent and baseline electrocardiogram (ECG) in current practice.
Loxapine is a dibenzoxazepine with intermediate potency, notable primarily because its receptor binding profile, including meaningful 5-HT2A blockade in addition to D2 antagonism, anticipates the pharmacological rationale later used to define atypical antipsychotics. Some investigators have classified loxapine as an atypical agent on receptor pharmacological grounds, though it was developed and approved as a conventional FGA.2 An inhaled formulation of loxapine (Adasuve) was subsequently approved for acute treatment of agitation in adults with schizophrenia or bipolar disorder, delivering rapid CNS drug levels via pulmonary absorption and producing measurable calming effect within 10 minutes. Molindone is a dihydroindolone with a receptor profile distinct from other FGAs and an unusually favorable metabolic profile: it is one of the few antipsychotics consistently associated with weight neutrality or even modest weight loss, attributed to its lack of H1 blocking activity and possible effects on appetite regulation. Both agents have limited contemporary use outside specific clinical niches.
FGAs share several pharmacokinetic features as a class. All are highly lipophilic and protein-bound, extensively distributed into tissues including the brain, and subject to hepatic first-pass metabolism following oral administration. Oral bioavailability is variable and generally low to moderate, ranging from approximately 25 to 65% for most agents, because of extensive first-pass hepatic extraction.2 This low and variable oral bioavailability is a clinically important source of inter-individual pharmacokinetic variability and contributes to the unpredictability of dose-response relationships between patients. Cytochrome P450 (CYP) enzymes, principally CYP2D6, CYP3A4, and CYP1A2, are responsible for oxidative metabolism of most FGAs. CYP2D6 is particularly relevant for haloperidol and perphenazine: poor metabolizers (approximately 7 to 10% of the European-ancestry population) at this enzyme will achieve plasma concentrations two to three times higher than extensive metabolizers at the same dose, with proportionally increased EPS and other adverse effects.
Plasma half-lives of oral FGAs are generally long enough to support once- or twice-daily dosing in chronic management. Haloperidol has a half-life of 12 to 36 hours; fluphenazine hydrochloride 14 to 24 hours; perphenazine 8 to 12 hours; chlorpromazine 16 to 30 hours; thioridazine 10 to 36 hours. Active metabolites contribute to the effective duration of action for several agents: reduced haloperidol is the primary active metabolite of haloperidol and has partial D2 agonist properties, which may partially explain the paradoxical clinical observation that very high haloperidol concentrations can sometimes reduce antipsychotic response.2 Chlorpromazine generates multiple active metabolites with independent pharmacological activity, complicating dose-response prediction in chronic use.
The rationale for LAI antipsychotics is straightforward: non-adherence to oral medication is among the most powerful predictors of relapse in schizophrenia, with studies consistently showing that 40 to 60% of outpatients with schizophrenia are non-adherent to oral antipsychotics within the first year of treatment.6 LAI formulations replace the variable oral bioavailability and daily adherence requirement with a fixed pharmacokinetic profile established at each injection, converting adherence from a daily behavior into a periodic clinical contact. The two established FGA LAI formulations are haloperidol decanoate and fluphenazine decanoate, both esterified with fatty acids to create oil-based depot preparations that are slowly absorbed from the intramuscular injection site.
Haloperidol decanoate is administered every 4 weeks (monthly), with a loading strategy of 10 to 20 times the stabilized oral haloperidol dose, not to exceed 100 mg for the initial injection, followed by dose adjustment based on clinical response and tolerability. Steady-state plasma concentrations are reached after approximately 3 to 4 months of monthly injections. The peak-to-trough plasma concentration ratio is substantially smaller than with oral dosing, producing more stable exposure and reducing the oscillations in D2 occupancy that may contribute to symptom breakthrough and adverse effects with oral therapy.2 Fluphenazine decanoate is administered every 2 to 4 weeks, with a typical dose range of 12.5 to 50 mg per injection. Its shorter depot interval relative to haloperidol decanoate allows somewhat more flexible dose adjustment but requires more frequent clinic visits.
A clinically important pharmacokinetic consideration for FGA depots is that the LAI formulation does not change the receptor-binding profile or adverse effect type of the underlying drug; it changes only the delivery kinetics. A patient who experienced severe EPS on oral haloperidol will continue to experience EPS-prone receptor occupancy on haloperidol decanoate unless the effective dose is lower. The advantage of LAI therapy for adherence does not eliminate the need for careful dose optimization, and the longer washout time following a depot injection (weeks rather than hours for oral doses) means that dose-related adverse effects are slower to resolve when they occur.
The most clinically consequential pharmacokinetic interaction for FGAs involves CYP1A2, the enzyme responsible for oxidative metabolism of chlorpromazine and several other phenothiazines. Cigarette smoking strongly induces CYP1A2, reducing plasma concentrations of CYP1A2-substrate antipsychotics by 30 to 50% in heavy smokers compared with non-smokers.2 The clinical implication runs in both directions: a patient stabilized on chlorpromazine while smoking may show apparent loss of efficacy if they stop smoking and their plasma levels rise, or may experience toxicity if admitted to a smoke-free inpatient unit without dose adjustment. This CYP1A2-smoking interaction becomes even more consequential for clozapine and olanzapine, which are more heavily CYP1A2-dependent, and is discussed in depth in CNS-Antipsy-03. Establishing a patient's smoking status at every outpatient visit is therefore not merely a general health measure; it is a pharmacokinetically relevant clinical data point for any patient on a CYP1A2-substrate antipsychotic.
Extrapyramidal side effects (EPS) are the most clinically consequential acute adverse effects of FGAs and represent the primary reason patients discontinue treatment against medical advice. They arise from D2 receptor blockade in the nigrostriatal pathway, which reduces dopaminergic tone in the striatum and disrupts the normal balance between dopaminergic and cholinergic neurotransmission in the basal ganglia. The four major EPS syndromes differ in their time course, underlying mechanism, and management approach, and must be distinguished from one another and from symptoms of the underlying psychiatric disorder before treatment decisions are made.2
Acute dystonia consists of sudden, sustained, and often painful muscle contractions producing abnormal postures. The most common presentations include oculogyric crisis (forced upward deviation of the eyes), torticollis (neck muscle spasm with head rotation), opisthotonus (arching of the back), and laryngeal or pharyngeal dystonia (the most dangerous form, capable of compromising the airway). Acute dystonia typically emerges within hours to 5 days of initiating an FGA or increasing the dose, representing the earliest EPS manifestation. Young males and antipsychotic-naive patients are at highest risk.2 The mechanism involves an acute reduction in striatal DA tone that unmasks a relative cholinergic excess in the basal ganglia. Treatment is highly effective: IM or IV diphenhydramine (25 to 50 mg) or benztropine (1 to 2 mg) produces rapid relief, typically within 15 to 30 minutes. Oral anticholinergic prophylaxis during the first 2 weeks of FGA therapy is appropriate for high-risk patients (young males, high-potency agents, high doses), though routine prophylaxis in all patients is not recommended because of the cognitive and anticholinergic adverse effect burden.
Akathisia is a syndrome of motor restlessness with a subjective sense of inner tension and compulsion to move. Patients may pace, shift weight from foot to foot, or be unable to sit or stand still. The subjective distress can be severe and is among the adverse effects most commonly cited by patients as a reason for non-adherence or self-discontinuation of antipsychotic treatment. Akathisia typically emerges within days to weeks of FGA initiation and can be mistaken for psychomotor agitation, worsening psychosis, or anxiety, leading to the clinical error of increasing the antipsychotic dose and thereby worsening the akathisia.2 The pathophysiology involves both dopaminergic and noradrenergic mechanisms; D2 blockade in mesolimbic and possibly mesocortical areas may contribute, distinct from the purely nigrostriatal mechanism of dystonia and parkinsonism.
Management of akathisia begins with dose reduction if clinically feasible. Propranolol, a non-selective beta-adrenergic antagonist, at doses of 30 to 80 mg per day, is the most evidence-supported pharmacological treatment and is particularly effective for the subjective restlessness component.2 Anticholinergic agents are less consistently effective for akathisia than for dystonia or parkinsonism and should not be the first-line intervention. Benzodiazepines provide short-term relief but are not appropriate for chronic management. Mirtazapine at low doses (7.5 to 15 mg) has shown benefit in several trials, likely through 5-HT2A and H1 mechanisms. If akathisia persists despite these measures, switching to a lower-EPS antipsychotic is the most appropriate long-term strategy.
Drug-induced parkinsonism (DIP) produces a clinical syndrome indistinguishable from idiopathic Parkinson disease (PD): bradykinesia, rigidity, resting tremor (though tremor is less common than in idiopathic PD), masked facies, and reduced arm swing. It typically emerges within days to weeks of FGA initiation and is dose-dependent. Elderly patients are at substantially higher risk, both because of age-related reduction in nigrostriatal dopaminergic reserve and because of reduced compensatory capacity. The distinction between DIP and idiopathic PD can be difficult; a useful clinical clue is that DIP is typically bilateral from the outset while idiopathic PD is asymmetric in its early course, and DIP improves within weeks to months of dose reduction or drug discontinuation.2
Management of DIP favors dose reduction or switching to a lower-EPS agent as the preferred approach. Anticholinergic agents (benztropine 0.5 to 2 mg twice daily; trihexyphenidyl 2 to 5 mg twice daily) reduce DIP symptoms but carry significant cognitive and peripheral anticholinergic adverse effects, are particularly hazardous in elderly patients, and should be used at the lowest effective dose for the shortest necessary duration. Amantadine, which has both dopaminergic and glutamatergic mechanisms, is an alternative with a more favorable cognitive profile than anticholinergics and may be preferred in patients where cognitive effects are a particular concern.
Neuroleptic malignant syndrome (NMS) is a rare but potentially fatal idiosyncratic reaction to antipsychotic agents characterized by a tetrad of hyperthermia, severe muscle rigidity, autonomic instability (fluctuating blood pressure, tachycardia, diaphoresis), and altered consciousness. It occurs in approximately 0.01 to 0.02% of patients treated with FGAs, with haloperidol and fluphenazine among the most frequently implicated agents.8 NMS can occur at any point during treatment but is most common in the first weeks and at times of rapid dose escalation. The mechanism is not fully established but is thought to involve rapid, extensive D2 receptor blockade in the nigrostriatal pathway (producing rigidity and hyperthermia through impaired heat dissipation from rigid muscles) and in the hypothalamus (disrupting thermoregulatory control). A concurrent central serotonergic contribution may exist, which partially explains the clinical overlap with serotonin syndrome.
The distinction between NMS and serotonin syndrome is clinically important because their management differs. NMS is characterized by lead-pipe rigidity, slow onset over 24 to 72 hours, and bradyreflexia, while serotonin syndrome features hyperreflexia, clonus, and more rapid onset, often within hours of precipitating drug exposure. Creatine kinase (CK) is typically markedly elevated in NMS (often exceeding 10,000 U/L) and may be elevated but less dramatically in serotonin syndrome.8 Management of NMS requires immediate discontinuation of all antipsychotic agents, aggressive supportive care including IV hydration, external cooling, and monitoring for rhabdomyolysis and acute kidney injury (AKI). Dantrolene (a skeletal muscle relaxant acting on ryanodine receptors) at 1 to 2.5 mg/kg IV reduces rigidity and hyperthermia. Bromocriptine (2.5 to 10 mg three times daily) or amantadine may be used to restore central dopaminergic tone. The antipsychotic should not be restarted for at least 2 weeks after complete NMS resolution; when reintroduction is necessary, a lower-potency agent at a lower dose with gradual titration is preferred, with close monitoring for recurrence.
Tardive dyskinesia (TD) is a movement disorder characterized by involuntary, repetitive, purposeless movements that develop after prolonged exposure to DA receptor-blocking agents. The most common presentation involves choreiform movements of the orolingual region: lip smacking, tongue protrusion, chewing movements, and facial grimacing. Choreoathetoid movements of the limbs, trunk rocking, and respiratory dyskinesias can also occur. TD typically emerges after months to years of antipsychotic exposure and, in a clinically deceptive pattern, may first become apparent or worsen when the antipsychotic dose is reduced or discontinued, because dose reduction unmasks receptor supersensitivity that had been compensatorily concealed by ongoing D2 blockade.9 This temporal pattern, called withdrawal-emergent or unmasking dyskinesia, can cause the clinical error of concluding that dose reduction caused the dyskinesia, when in fact the dyskinesia was preexisting but was suppressed by blockade at supersensitive receptors.
The pathophysiology involves dopamine receptor supersensitivity in the striatum developing in response to chronic D2 blockade. Postsynaptic D2 receptors upregulate in density and sensitivity over time, and when this supersensitivity becomes sufficiently marked and persistent, it manifests as involuntary movements even in the presence of continued antipsychotic therapy.9 Risk factors include older age, female sex, longer duration of FGA exposure, higher cumulative dose, presence of early EPS, and a history of affective disorder. The annual incidence of TD in patients maintained on FGAs is approximately 5% per year for the first several years of treatment, with cumulative risk approaching 20 to 30% after 5 years in populations treated with high-potency FGAs.9
The assessment of TD severity uses the Abnormal Involuntary Movement Scale (AIMS), a standardized rating instrument that should be administered at baseline and at regular intervals (every 6 months) in any patient receiving chronic antipsychotic therapy. When TD is identified, the first management step is to minimize antipsychotic dose where clinically feasible or switch to an SGA with lower TD risk. The only FDA-approved pharmacological treatments specifically for TD are valbenazine and deutetrabenazine, both selective vesicular monoamine transporter 2 (VMAT2) inhibitors that reduce presynaptic DA release by depleting synaptic DA stores, thereby reducing the excessive dopaminergic stimulation at supersensitive receptors.7,10 These agents have demonstrated clinically meaningful reductions in AIMS scores in randomized trials and represent a genuine advance in the management of a previously difficult-to-treat condition.
FGAs consistently elevate prolactin through tuberoinfundibular D2 blockade, as described in CNS-Antipsy-01. Clinical consequences in women include galactorrhea, amenorrhea, and dyspareunia; in men, gynecomastia, galactorrhea, and sexual dysfunction including reduced libido and erectile impairment. Sustained hyperprolactinemia of greater than 12 to 24 months duration is associated with reduced bone mineral density and increased fracture risk, representing an underrecognized long-term consequence of chronic FGA therapy, particularly in premenopausal women.2 Monitoring of prolactin levels at baseline and during treatment is appropriate in any patient on a prolactin-elevating antipsychotic who develops relevant symptoms. Epileptic seizure threshold lowering is a class effect of most FGAs, most pronounced with chlorpromazine and loxapine; patients with pre-existing epilepsy require closer monitoring and may need antiepileptic dose adjustment. Weight gain with FGAs is generally less severe than with some SGAs, though chlorpromazine and thioridazine produce meaningful weight gain through H1 blockade and appetite stimulation.
Schizophrenia and schizoaffective disorder remain the primary indications for FGAs. In acute psychosis requiring rapid D2 blockade, particularly in the inpatient setting, haloperidol is the most commonly used FGA because of its predictable pharmacokinetics, extensive safety data, and availability in IM and IV formulations. The combination of haloperidol with a benzodiazepine (lorazepam 1 to 2 mg IM) for acute agitation produces faster and more reliable sedation than either agent alone and is a widely used protocol in emergency psychiatry and general hospital medicine.11 The addition of diphenhydramine to this combination reduces the risk of acute dystonia in antipsychotic-naive patients.
For maintenance treatment of chronic schizophrenia, the choice between an FGA and an SGA requires individualized assessment. In patients who have responded to and tolerated a specific FGA without significant EPS or TD, continuing that agent is reasonable. In patients with prominent negative symptoms or cognitive deficits, switching to an SGA with better evidence for these domains is justifiable. In patients with adherence difficulties, the availability of established and inexpensive FGA LAI formulations (haloperidol decanoate, fluphenazine decanoate) may tip the balance toward an FGA, particularly if the cost of SGA LAI formulations is prohibitive. The CATIE study results, demonstrating that perphenazine performed comparably to several SGAs on all-cause discontinuation, support the continued use of FGAs as a pharmacoeconomically defensible choice in appropriate patients.4
FGAs retain specific indications beyond schizophrenia in which their D2-blocking properties are directly therapeutic. Tourette syndrome responds to low-dose haloperidol or pimozide (a diphenylbutylpiperidine FGA with particularly selective D2 affinity and some evidence for tic suppression), though the risk-benefit analysis must weigh chronic EPS and QTc risks against symptom burden.2 Haloperidol is used for delirium management in medically ill inpatients, where its lack of significant anticholinergic activity is an advantage over low-potency agents. Droperidol, a short-acting butyrophenone, is used for procedural sedation and postoperative nausea and vomiting at sub-antipsychotic doses. Prochlorperazine and promethazine, phenothiazine derivatives with primarily antiemetic indications, act through D2 blockade in the chemoreceptor trigger zone and are routinely used in emergency medicine for nausea and vestibular disorders.
The decision to use an FGA requires explicit attention to monitoring. Patients initiated on any FGA should have baseline ECG if thioridazine or pimozide is being considered, baseline AIMS assessment to document any pre-existing movement abnormalities, and documentation of informed consent regarding EPS and TD risk. Serum prolactin measurement is warranted if symptoms of hyperprolactinemia develop. Fasting glucose and lipid assessment is less critical for FGAs than for metabolically active SGAs but remains part of comprehensive cardiometabolic monitoring in any patient on long-term antipsychotic therapy. CYP2D6 genotyping is not routinely performed but should be considered in patients who exhibit unexpectedly high adverse effect burden at standard FGA doses, as poor metabolizer status substantially elevates plasma concentrations of haloperidol and perphenazine.2
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