Chemistry and Pharmacodynamics

Neurotransmitters that may be modulated by antipsychotics for a therapeutic effect includedopamineDopamineOne of the catecholamine neurotransmitters in the brain. It is derived from tyrosine and is the precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement.Receptors and Neurotransmitters of the CNS,serotoninSerotoninA biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity.Receptors and Neurotransmitters of the CNS (also called5-hydroxytryptamine5-hydroxytryptamineA biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity.Receptors and Neurotransmitters of the CNS (5-HT5-HTA biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity.Receptors and Neurotransmitters of the CNS)), andnorepinephrineNorepinephrinePrecursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers, and of the diffuse projection system in the brain that arises from the locus ceruleus.Receptors and Neurotransmitters of the CNS (NE).

Mechanism of action

• Blockadeof postsynapticdopamineDopamineOne of the catecholamine neurotransmitters in the brain. It is derived from tyrosine and is the precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement.Receptors and Neurotransmitters of the CNS D₂receptorsReceptorsReceptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell.Receptors in themesolimbic pathway →reliefofpsychotic symptomsPsychotic symptomsBrief Psychotic Disorder
• Blockade inmesocortical, nigrostriatal, and tuberoinfundibular pathways →adverseeffects
• Low-potency agents have a greater affinity for:
  • Alpha-adrenergicreceptorsReceptorsReceptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell.Receptors
  • HistaminergicreceptorsReceptorsReceptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell.Receptors
  • Muscarinic receptorsMuscarinic ReceptorsAsthma Drugs

Physiologic effects

• DopaminergicreceptorsReceptorsReceptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell.Receptors:
  • Subtypes D₁ and D₂ are pharmacologic targets.
  • D₁-likereceptorsReceptorsReceptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell.Receptors are excitatory.
  • D₂-likereceptorsReceptorsReceptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell.Receptors are inhibitory.
  • D₂receptorsReceptorsReceptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell.Receptors are expressed on dopaminergicneuronsNeuronsThe basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system.Nervous System: Histology as presynaptic and postsynapticreceptorsReceptorsReceptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell.Receptors.
• DopamineDopamineOne of the catecholamine neurotransmitters in the brain. It is derived from tyrosine and is the precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement.Receptors and Neurotransmitters of the CNShypothesisHypothesisA hypothesis is a preliminary answer to a research question (i.e., a “guess” about what the results will be). There are 2 types of hypotheses: the null hypothesis and the alternative hypothesis.Statistical Tests and Data Representation ofschizophreniaSchizophreniaSchizophrenia is a chronic mental health disorder characterized by the presence of psychotic symptoms such as delusions or hallucinations. The signs and symptoms of schizophrenia are traditionally separated into 2 groups: positive (delusions, hallucinations, and disorganized speech or behavior) and negative (flat affect, avolition, anhedonia, poor attention, and alogia).Schizophrenia:
  • DopamineDopamineOne of the catecholamine neurotransmitters in the brain. It is derived from tyrosine and is the precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement.Receptors and Neurotransmitters of the CNShyperfunction in thestriatumStriatumStriped gray matter and white matter consisting of the neostriatum and paleostriatum (globus pallidus). It is located in front of and lateral to the thalamus in each cerebral hemisphere. The gray substance is made up of the caudate nucleus and the lentiform nucleus (the latter consisting of the globus pallidus and putamen). The white matter is the internal capsule.Basal Ganglia: Anatomy (mesolimbic tract) → “positive symptoms”; 1st-generation antipsychotics (FGAs) reduce:
    • Delusions
    • HallucinationsHallucinationsSubjectively experienced sensations in the absence of an appropriate stimulus, but which are regarded by the individual as real. They may be of organic origin or associated with mental disorders.Schizophrenia
    • Paranoia
    • ManiaManiaA state of elevated excitement with over-activity sometimes accompanied with psychotic symptoms (e.g., psychomotor agitation, inflated self esteem and flight of ideas). It is often associated with mental disorders (e.g., cyclothymic disorder; and bipolar diseases).Bipolar Disorder
    • Aggressiveness
  • DopamineDopamineOne of the catecholamine neurotransmitters in the brain. It is derived from tyrosine and is the precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement.Receptors and Neurotransmitters of the CNShypofunction in the prefrontal cortex (mesocorticaltract) →negative and cognitive symptoms:
    • Blunted affect,anhedoniaAnhedoniaInability to experience pleasure due to impairment or dysfunction of normal psychological and neurobiological mechanisms. It is a symptom of many psychotic disorders (e.g., depressive disorder, major; and schizophrenia).Schizophrenia,avolitionAvolitionLack of initiative.Schizophrenia, social withdrawal
    • Impairment ofattentionAttentionFocusing on certain aspects of current experience to the exclusion of others. It is the act of heeding or taking notice or concentrating.Psychiatric Assessment, workingmemoryMemoryComplex mental function having four distinct phases: (1) memorizing or learning, (2) retention, (3) recall, and (4) recognition. Clinically, it is usually subdivided into immediate, recent, and remote memory.Psychiatric Assessment, and executive function
  • High doses of psychostimulants can cause psychosis.
• Effects of increasingdopamineDopamineOne of the catecholamine neurotransmitters in the brain. It is derived from tyrosine and is the precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement.Receptors and Neurotransmitters of the CNS in the other 2 dopaminergic tracts in thebrainBrainThe part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem.Nervous System: Anatomy, Structure, and Classification:
  • In the nigrostriatal tract: improves extrapyramidal function such as symptoms ofParkinson diseaseParkinson diseaseParkinson’s disease (PD) is a chronic, progressive neurodegenerative disorder. Although the cause is unknown, several genetic and environmental risk factors are currently being studied. Individuals present clinically with resting tremor, bradykinesia, rigidity, and postural instability.Parkinson’s Disease
  • In the chemoreceptor zone (vomitingVomitingThe forcible expulsion of the contents of the stomach through the mouth.Hypokalemia center of thebrainBrainThe part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem.Nervous System: Anatomy, Structure, and Classification):anorexiaAnorexiaThe lack or loss of appetite accompanied by an aversion to food and the inability to eat. It is the defining characteristic of the disorder anorexia nervosa.Anorexia Nervosa,nauseaNauseaAn unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses.Antiemetics/vomitingVomitingThe forcible expulsion of the contents of the stomach through the mouth.Hypokalemia
• Serotonergic (5-HT5-HTA biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity.Receptors and Neurotransmitters of the CNS)receptorsReceptorsReceptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell.Receptors:
  • Major serotonin-producingneuronsNeuronsThe basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system.Nervous System: Histology are located in therapheRapheTesticles: Anatomy nuclei in the brainstem.
  • 5-HT5-HTA biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity.Receptors and Neurotransmitters of the CNS is synthesized in serotonergic nerve terminals:
    • Upon thepropagationPropagationPropagation refers to how the electrical signal spreads to every myocyte in the heart.Cardiac Physiology of anaction potentialAction PotentialAbrupt changes in the membrane potential that sweep along the cell membrane of excitable cells in response to excitation stimuli.Membrane Potential down the neuron → storagevesiclesVesiclesFemale Genitourinary Examination fuse with thepresynaptic membranePresynaptic membraneSynapses and Neurotransmission →release neurotransmitters into thesynaptic cleftSynaptic cleftSynapses and Neurotransmission 
    • 5-HT5-HTA biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity.Receptors and Neurotransmitters of the CNSactivity is terminated by theserotoninSerotoninA biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity.Receptors and Neurotransmitters of the CNS transporter → reuptake of5-HT5-HTA biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity.Receptors and Neurotransmitters of the CNS into the serotonergic nerve terminal
    • 5-HT5-HTA biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity.Receptors and Neurotransmitters of the CNS can then be reloaded intovesiclesVesiclesFemale Genitourinary Examination or metabolized on the outer mitochondrial membrane in nerve terminals.
• SerotoninSerotoninA biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity.Receptors and Neurotransmitters of the CNShypothesisHypothesisA hypothesis is a preliminary answer to a research question (i.e., a “guess” about what the results will be). There are 2 types of hypotheses: the null hypothesis and the alternative hypothesis.Statistical Tests and Data Representation ofschizophreniaSchizophreniaSchizophrenia is a chronic mental health disorder characterized by the presence of psychotic symptoms such as delusions or hallucinations. The signs and symptoms of schizophrenia are traditionally separated into 2 groups: positive (delusions, hallucinations, and disorganized speech or behavior) and negative (flat affect, avolition, anhedonia, poor attention, and alogia).Schizophrenia: Hyperactivation of cortical5-HT5-HTA biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity.Receptors and Neurotransmitters of the CNS_2AreceptorsReceptorsReceptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell.Receptors on glutamatergic pyramidalneuronsNeuronsThe basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system.Nervous System: Histology → ↑glutamateGlutamateDerivatives of glutamic acid. Included under this heading are a broad variety of acid forms, salts, esters, and amides that contain the 2-aminopentanedioic acid structure.Synthesis of Nonessential Amino Acids release in the ventral tegmental area (VTA) → overactivation of the mesolimbic pathway → ↑dopamineDopamineOne of the catecholamine neurotransmitters in the brain. It is derived from tyrosine and is the precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement.Receptors and Neurotransmitters of the CNS release in thestriatumStriatumStriped gray matter and white matter consisting of the neostriatum and paleostriatum (globus pallidus). It is located in front of and lateral to the thalamus in each cerebral hemisphere. The gray substance is made up of the caudate nucleus and the lentiform nucleus (the latter consisting of the globus pallidus and putamen). The white matter is the internal capsule.Basal Ganglia: Anatomy

Pharmacokinetics and Classification

PharmacokineticsPharmacokineticsPharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body.Pharmacokinetics and Pharmacodynamics

There are numerous medications with uniquepharmacokineticsPharmacokineticsPharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body.Pharmacokinetics and Pharmacodynamics.

• FGAs act at the D2receptorReceptorReceptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell.Receptors.
• Well absorbed:
  • Cross theblood-brain barrierBlood-brain barrierSpecialized non-fenestrated tightly-joined endothelial cells with tight junctions that form a transport barrier for certain substances between the cerebral capillaries and the brain tissue.Systemic and Special Circulations easily
  • Have long half-lives:
    • Half-lives of orally administered drugs vary from 30 hours (chlorpromazine) to 55 hours (pimozide).
    • IM dosing of some FGAs (e.g., thehalf-lifeHalf-LifeThe time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity.Pharmacokinetics and Pharmacodynamics of IM haloperidol decanoate is 3 weeks; dosed monthly)
  • Cytochrome P450Cytochrome P450A superfamily of hundreds of closely related hemeproteins found throughout the phylogenetic spectrum, from animals, plants, fungi, to bacteria. They include numerous complex monooxygenases (mixed function oxygenases). In animals, these p450 enzymes serve two major functions: (1) biosynthesis of steroids, fatty acids, and bile acids; (2) metabolism of endogenous and a wide variety of exogenous substrates, such as toxins and drugs (biotransformation). They are classified, according to their sequence similarities rather than functions, into cyp gene families (>40% homology) and subfamilies (>59% homology). For example, enzymes from the cyp1, cyp2, and cyp3 gene families are responsible for most drug metabolism.Drug-Induced Liver Injury (CYP) inhibitors will prolong the action of FGAs:
    • Different FGAs use any or all of the CYP2D6, 3A4, and 1A2 pathways.
    • Other medications that aresubstrates for these pathways may cause overdose symptoms.
• FGAs need 1–2 weeks for full effect.
• All FGAs except haloperidol block the H1 histaminereceptorReceptorReceptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell.Receptors.
• Highly lipid-soluble compounds, some of which can be used as a long-acting injection (every 2–4 weeks)
• EliminationEliminationThe initial damage and destruction of tumor cells by innate and adaptive immunity. Completion of the phase means no cancer growth.Cancer Immunotherapy: excreted in the urine and feces

Classification

The FGAs can be classified based on their potency:

• High-potency FGAs:
  • Low activity at the histaminic andmuscarinic receptorsMuscarinic ReceptorsAsthma Drugs
  • Minimally associated with the following adverse effects:
    • Sedation
    • Weight gain
    • AnticholinergicAnticholinergicAnticholinergic drugs block the effect of the neurotransmitter acetylcholine at the muscarinic receptors in the central and peripheral nervous systems. Anticholinergic agents inhibit the parasympathetic nervous system, resulting in effects on the smooth muscle in the respiratory tract, vascular system, urinary tract, GI tract, and pupils of the eyes.Anticholinergic Drugs activity
  • High risk for extrapyramidal side effects (EPS) withallof the high-potency FGAs:
    • DystoniaDystoniaDystonia is a hyperkinetic movement disorder characterized by the involuntary contraction of muscles, resulting in abnormal postures or twisting and repetitive movements. Dystonia can present in various ways as may affect many different skeletal muscle groups.Dystonia
    • BradykinesiaBradykinesiaParkinson’s Disease
    • Akathisia
  • Examples:
    • Fluphenazine (Prolixin)
    • Haloperidol (Haldol)
    • Loxapine (Loxitane)
    • Perphenazine (generic)
    • Pimozide (Orap)
    • Thiothixene (Navane)
    • Trifluoperazine (Stelazine)
• Low-potency FGAs:
  • Lower affinity fordopamineDopamineOne of the catecholamine neurotransmitters in the brain. It is derived from tyrosine and is the precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement.Receptors and Neurotransmitters of the CNSreceptorsReceptorsReceptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell.Receptors; thus, higher doses are needed
  • HigherincidenceIncidenceThe number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time.Measures of Disease Frequency ofanticholinergicAnticholinergicAnticholinergic drugs block the effect of the neurotransmitter acetylcholine at the muscarinic receptors in the central and peripheral nervous systems. Anticholinergic agents inhibit the parasympathetic nervous system, resulting in effects on the smooth muscle in the respiratory tract, vascular system, urinary tract, GI tract, and pupils of the eyes.Anticholinergic Drugs and antihistamine side effects
  • LowerincidenceIncidenceThe number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time.Measures of Disease Frequency of EPS andneuroleptic malignant syndromeNeuroleptic malignant syndromeNeuroleptic malignant syndrome (NMS) is a rare, idiosyncratic, and potentially life-threatening reaction to antipsychotic drugs. Neuroleptic malignant syndrome presents with ≥ 2 of the following cardinal symptoms: fever, altered mental status, muscle rigidity, and autonomic dysfunction.Neuroleptic Malignant Syndrome (NMSNMSNeuroleptic malignant syndrome (NMS) is a rare, idiosyncratic, and potentially life-threatening reaction to antipsychotic drugs. Neuroleptic malignant syndrome presents with ≥ 2 of the following cardinal symptoms: fever, altered mental status, muscle rigidity, and autonomic dysfunction.Neuroleptic Malignant Syndrome)
  • Examples:
    • Chlorpromazine (Thorazine)
    • Thioridazine (formerly Mellaril, the branded product was withdrawn worldwide in 2005 because it caused severe cardiac arrhythmias. However, generic versions are still available in the US.)

Indications

• Conditions treated using high-potency antipsychotics:
  • SchizophreniaSchizophreniaSchizophrenia is a chronic mental health disorder characterized by the presence of psychotic symptoms such as delusions or hallucinations. The signs and symptoms of schizophrenia are traditionally separated into 2 groups: positive (delusions, hallucinations, and disorganized speech or behavior) and negative (flat affect, avolition, anhedonia, poor attention, and alogia).Schizophrenia:
    • Reduces the “positive” symptoms (e.g., delusions, aggressiveness)
    • FGAs have few effects on the “negative” symptoms (e.g.,anhedoniaAnhedoniaInability to experience pleasure due to impairment or dysfunction of normal psychological and neurobiological mechanisms. It is a symptom of many psychotic disorders (e.g., depressive disorder, major; and schizophrenia).Schizophrenia, social withdrawal).
    • 2nd-generation antipsychotics: more effective at reducing neurocognitive impairment
  • Psychosis
  • ManiaManiaA state of elevated excitement with over-activity sometimes accompanied with psychotic symptoms (e.g., psychomotor agitation, inflated self esteem and flight of ideas). It is often associated with mental disorders (e.g., cyclothymic disorder; and bipolar diseases).Bipolar Disorder associated withbipolarBipolarNervous System: Histology disorder:
    • Used in conjunction withmood stabilizers(e.g.,lithiumLithiumAn element in the alkali metals family. It has the atomic symbol li, atomic number 3, and atomic weight [6. 938; 6. 997]. Salts of lithium are used in treating bipolar disorder.Ebstein’s Anomaly,valproic acidValproic acidA fatty acid with anticonvulsant and anti-manic properties that is used in the treatment of epilepsy and bipolar disorder. The mechanisms of its therapeutic actions are not well understood. It may act by increasing gamma-aminobutyric acid levels in the brain or by altering the properties of voltage-gated sodium channels.First-Generation Anticonvulsant Drugs, andlamotrigineLamotrigineA phenyltriazine compound, sodium and calcium channel blocker that is used for the treatment of seizures and bipolar disorder.Second-Generation Anticonvulsant Drugs)
    • FGAs act rapidly → antimanic effect (mood stabilizers have a latency period before they take effect)
  • Tic disorder (Tourette syndromeTourette SyndromeA neuropsychological disorder related to alterations in dopamine metabolism and neurotransmission involving frontal-subcortical neuronal circuits. Both multiple motor and one or more vocal tics need to be present with tics occurring many times a day, nearly daily, over a period of more than one year. The onset is before age 18 and the disturbance is not due to direct physiological effects of a substance or another medical condition. The disturbance causes marked distress or significant impairment in social, occupational, or other important areas of functioning.Tics and Tourette Syndrome)
  • Treatment-resistant depression:adjuvantAdjuvantSubstances that augment, stimulate, activate, potentiate, or modulate the immune response at either the cellular or humoral level. The classical agents (freund’s adjuvant, bcg, corynebacterium parvum, et al.) contain bacterial antigens. Some are endogenous (e.g., histamine, interferon, transfer factor, tuftsin, interleukin-1). Their mode of action is either non-specific, resulting in increased immune responsiveness to a wide variety of antigens, or antigen-specific, i.e., affecting a restricted type of immune response to a narrow group of antigens. The therapeutic efficacy of many biological response modifiers is related to their antigen-specific immunoadjuvanticity.Vaccination therapy in combination with anantidepressantAntidepressantAntidepressants encompass several drug classes and are used to treat individuals with depression, anxiety, and psychiatric conditions, as well as those with chronic pain and symptoms of menopause. Antidepressants include selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and many other drugs in a class of their own.Serotonin Reuptake Inhibitors and Similar Antidepressants
  • DementiaDementiaMajor neurocognitive disorders (NCD), also known as dementia, are a group of diseases characterized by decline in a person’s memory and executive function. These disorders are progressive and persistent diseases that are the leading cause of disability among elderly people worldwide.Major Neurocognitive Disorders:
    • Used cautiously in individuals with severedementiaDementiaMajor neurocognitive disorders (NCD), also known as dementia, are a group of diseases characterized by decline in a person’s memory and executive function. These disorders are progressive and persistent diseases that are the leading cause of disability among elderly people worldwide.Major Neurocognitive Disorders
    • Used in individuals who are aggressive or pose danger to themselves or others
• Low-potency antipsychotics: chlorpromazine (Thorazine)
  • Used for the same conditions listed above
    • Used to relieve prolonged hiccups
    • Used to treat severe behavioral problems in children
  • Reduces aggressive behavior,hallucinationsHallucinationsSubjectively experienced sensations in the absence of an appropriate stimulus, but which are regarded by the individual as real. They may be of organic origin or associated with mental disorders.Schizophrenia, suicidal/homicidal thoughts

Adverse Effects

The adverse effects of FGAs are due todopamineDopamineOne of the catecholamine neurotransmitters in the brain. It is derived from tyrosine and is the precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement.Receptors and Neurotransmitters of the CNS blockade.

• Low-potency FGAs (chlorpromazine and thioridazine) can cause:
  • Sedation
  • HypotensionHypotensionHypotension is defined as low blood pressure, specifically< 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause.Hypotension
  • AnticholinergicAnticholinergicAnticholinergic drugs block the effect of the neurotransmitter acetylcholine at the muscarinic receptors in the central and peripheral nervous systems. Anticholinergic agents inhibit the parasympathetic nervous system, resulting in effects on the smooth muscle in the respiratory tract, vascular system, urinary tract, GI tract, and pupils of the eyes.Anticholinergic Drugs side effects:
    • Dry mouth
    • DizzinessDizzinessAn imprecise term which may refer to a sense of spatial disorientation, motion of the environment, or lightheadedness.Lateral Medullary Syndrome (Wallenberg Syndrome)
    • Blurred visionBlurred VisionRetinal Detachment
    • TachycardiaTachycardiaAbnormally rapid heartbeat, usually with a heart rate above 100 beats per minute for adults. Tachycardia accompanied by disturbance in the cardiac depolarization (cardiac arrhythmia) is called tachyarrhythmia.Sepsis in Children
    • DeliriumDeliriumDelirium is a medical condition characterized by acute disturbances in attention and awareness. Symptoms may fluctuate during the course of a day and involve memory deficits and disorientation.Delirium
    • HallucinationsHallucinationsSubjectively experienced sensations in the absence of an appropriate stimulus, but which are regarded by the individual as real. They may be of organic origin or associated with mental disorders.Schizophrenia
• High-potency FGAs have ahigh risk of EPS:
  • AcutedystoniaDystoniaDystonia is a hyperkinetic movement disorder characterized by the involuntary contraction of muscles, resulting in abnormal postures or twisting and repetitive movements. Dystonia can present in various ways as may affect many different skeletal muscle groups.Dystonia: prolonged tonic musclespasmsSpasmsAn involuntary contraction of a muscle or group of muscles. Spasms may involve skeletal muscle or smooth muscle.Ion Channel Myopathy of rapid onset upon initiating (1st 4 days) or increasing the dose of antipsychotics
  • BradykinesiaBradykinesiaParkinson’s Disease (Parkinsonian symptom)
  • Akathisia (feeling of restlessness)
  • Perphenazine (generic): associated with a lower rate ofextrapyramidal symptomsExtrapyramidal SymptomsAtaxia-telangiectasia than that with high-potency FGA haloperidol; comparable withrisperidoneRisperidoneA selective blocker of dopamine D2 receptors and serotonin 5-HT2 receptors that acts as an atypical antipsychotic agent. It has been shown to improve both positive and negative symptoms in the treatment of schizophrenia.Second-Generation Antipsychotics
• Weight gain
• ElevatedliverLiverThe liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood.Liver: AnatomyenzymesEnzymesEnzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules.Basics of Enzymes
• Ophthalmologic problems:
  • Retinitis pigmentosa (rare)
  • WorsenedglaucomaGlaucomaGlaucoma is an optic neuropathy characterized by typical visual field defects and optic nerve atrophy seen as optic disc cupping on examination. The acute form of glaucoma is a medical emergency. Glaucoma is often, but not always, caused by increased intraocular pressure (IOP).Glaucoma
• “Anti-HAM” symptoms:
  • H: Anti-Histamine symptoms:
    • Sedation
    • SeizuresSeizuresA seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized.Seizures
    • DizzinessDizzinessAn imprecise term which may refer to a sense of spatial disorientation, motion of the environment, or lightheadedness.Lateral Medullary Syndrome (Wallenberg Syndrome)
    • Dry mouth
  • A: Anti-Alpha-adrenergic symptoms:
    • Orthostatic hypotensionOrthostatic hypotensionA significant drop in blood pressure after assuming a standing position. Orthostatic hypotension is a finding, and defined as a 20-mm hg decrease in systolic pressure or a 10-mm hg decrease in diastolic pressure 3 minutes after the person has risen from supine to standing. Symptoms generally include dizziness, blurred vision, and syncope.Hypotension
    • Arrhythmias
    • Sexual dysfunctionSexual dysfunctionPhysiological disturbances in normal sexual performance in either the male or the female.Sexual Physiology
  • M: Anti-Muscarinic symptoms:
    • Dry mouth
    • TachycardiaTachycardiaAbnormally rapid heartbeat, usually with a heart rate above 100 beats per minute for adults. Tachycardia accompanied by disturbance in the cardiac depolarization (cardiac arrhythmia) is called tachyarrhythmia.Sepsis in Children
    • Urinary retentionUrinary retentionInability to empty the urinary bladder with voiding (urination).Delirium
    • Blurred visionBlurred VisionRetinal Detachment
    • ConstipationConstipationConstipation is common and may be due to a variety of causes. Constipation is generally defined as bowel movement frequency< 3 times per week. Patients who are constipated often strain to pass hard stools. The condition is classified as primary (also known as idiopathic or functional constipation) or secondary, and as acute or chronic.Constipation
• Tardive dyskinesia:
  • Due to postsynapticdopamineDopamineOne of the catecholamine neurotransmitters in the brain. It is derived from tyrosine and is the precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement.Receptors and Neurotransmitters of the CNSreceptorReceptorReceptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell.Receptors hypersensitivity
  • May take years or decades to appear
  • Usuallypermanent and distressing to affected individuals
  • Manifestations:
    • Abnormal, involuntary, hyperkinetic movements
    • Usually affects the mouth andtongueTongueThe tongue, on the other hand, is a complex muscular structure that permits tasting and facilitates the process of mastication and communication. The blood supply of the tongue originates from the external carotid artery, and the innervation is through cranial nerves.Lips and Tongue: Anatomy, but can also affect the trunk
    • Irreversible facial disfiguration
• NMSNMSNeuroleptic malignant syndrome (NMS) is a rare, idiosyncratic, and potentially life-threatening reaction to antipsychotic drugs. Neuroleptic malignant syndrome presents with ≥ 2 of the following cardinal symptoms: fever, altered mental status, muscle rigidity, and autonomic dysfunction.Neuroleptic Malignant Syndrome:
  • Life-threatening reaction to FGAs
  • Causes hyperthermia (very highfeverFeverFever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin.Fever)
  • Other symptoms:
    • Confusion
    • Muscle rigidityMuscle rigidityContinuous involuntary sustained muscle contraction which is often a manifestation of basal ganglia diseases. When an affected muscle is passively stretched, the degree of resistance remains constant regardless of the rate at which the muscle is stretched. This feature helps to distinguish rigidity from muscle spasticity.Motor Neuron Lesions
    • Diaphoresis
    • TachycardiaTachycardiaAbnormally rapid heartbeat, usually with a heart rate above 100 beats per minute for adults. Tachycardia accompanied by disturbance in the cardiac depolarization (cardiac arrhythmia) is called tachyarrhythmia.Sepsis in Children
• HyperprolactinemiaHyperprolactinemiaHyperprolactinemia is defined as a condition of elevated levels of prolactin (PRL) hormone in the blood. The PRL hormone is secreted by the anterior pituitary gland and is responsible for breast development and lactation. The most common cause is PRL-secreting pituitary adenomas (prolactinomas).Hyperprolactinemia (andgalactorrheaGalactorrheaExcessive or inappropriate lactation in females or males, and not necessarily related to pregnancy. Galactorrhea can occur either unilaterally or bilaterally, and be profuse or sparse. Its most common cause is hyperprolactinemia.Hyperprolactinemia in both women and men)

Drug-Drug Interactions and Contraindications

Drug-drug interactions

• Antacids ↓absorptionAbsorptionAbsorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation.Digestion and Absorption of fluphenazine and trifluoperazine
• Avoid the use of FGAs with allQT-prolonging agents.
• CYP3A4CYP3A4Class 3 Antiarrhythmic Drugs (Potassium Channel Blockers) inducers interact with pimozide:
  • CarbamazepineCarbamazepineA dibenzazepine that acts as a sodium channel blocker. It is used as an anticonvulsant for the treatment of grand mal and psychomotor or focal seizures. It may also be used in the management of bipolar disorder, and has analgesic properties.First-Generation Anticonvulsant Drugs
  • Drug-food interaction with grapefruit juice
• CYP1A2 inhibitors interact with thiothixene and trifluoperazine.
• CYP2D6 inhibitors interact with perphenazine and chlorpromazine:
  • FluoxetineFluoxetineThe first highly specific serotonin uptake inhibitor. It is used as an antidepressant and often has a more acceptable side-effects profile than traditional antidepressants.Serotonin Reuptake Inhibitors and Similar Antidepressants
  • ParoxetineParoxetineA serotonin uptake inhibitor that is effective in the treatment of depression.Serotonin Reuptake Inhibitors and Similar Antidepressants
  • BupropionBupropionA propiophenone-derived antidepressant and antismoking agent that inhibits the uptake of dopamine.Other Antidepressants

ContraindicationsContraindicationsA condition or factor associated with a recipient that makes the use of a drug, procedure, or physical agent improper or inadvisable. Contraindications may be absolute (life threatening) or relative (higher risk of complications in which benefits may outweigh risks).Noninvasive Ventilation

• Beers list: a list of potentially inappropriate medications for use in the elderly
  • Originally published in 1991 and updated regularly
  • All antipsychotics are listed in the Beers list.
• Generalblack-box warning:All antipsychotics increase the risk of death in older individuals with dementia-related psychosis.
• CNS:
  • Individuals who are in acomaComaComa is defined as a deep state of unarousable unresponsiveness, characterized by a score of 3 points on the GCS. A comatose state can be caused by a multitude of conditions, making the precise epidemiology and prognosis of coma difficult to determine.Coma or with CNS depression
  • Concomitant high-dose hypnotics
  • Parkinson diseaseParkinson diseaseParkinson’s disease (PD) is a chronic, progressive neurodegenerative disorder. Although the cause is unknown, several genetic and environmental risk factors are currently being studied. Individuals present clinically with resting tremor, bradykinesia, rigidity, and postural instability.Parkinson’s Disease
• Cardiovascular:
  • Arrhythmias
  • Congenital long QT syndromeCongenital long QT syndromeLong QT Syndrome
• Hematologic:
  • Blood dyscrasias
  • Bone marrowBone marrowThe soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells.Bone Marrow: Composition and Hematopoiesis depression

References

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9. American Geriatrics Society. (2019). 2019 Updated AGS Beers Criteria® for Potentially Inappropriate Medication Use in Older Adults.Journal of the American Geriatric Society. 67, 674–694.https://doi.org/10.1111/jgs.15767 
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11. Lexicomp, Inc. (2021). Pimozide: Drug information. UpToDate. Retrieved November 19, 2025, fromhttps://www.uptodate.com/contents/pimozide-drug-information