How Do Second Generation Antipsychotics Work?

Second generation antipsychotics (SGAs), also known as atypical antipsychotics, are a newer class of antipsychotic medications used to treat schizophrenia, bipolar disorder and related psychiatric conditions. Second generation antipsychotics were developed to improve upon the efficacy and safety of first generation antipsychotics (FGAs).

Second generation antipsychotics work by blocking the excitatory activity of dopamine and serotonin, chemicals (neurotransmitters) released by nerve cells (neurons) to transmit nerve signals. Dopamine and serotonin regulate many functions including pleasure sensation, mood, behavior, learning and memory, among others.

While most FGAs block only D2 dopamine receptors, SGAs block both D2 receptors and 5-HT2A serotonin receptors. Receptors are protein molecules on the surface of neurons that initiate action when stimulated by these neurotransmitters. D2 and 5-HT2A receptors are types of excitatory receptors, believed to be involved in psychosis.

Some SGAs work by also stimulating 5-HT1 serotonin receptors, which are inhibitory receptors, in addition to blocking 5-HT2A receptors. SGAs also have effects on other neurotransmitters such as norepinephrine.

Second generation antipsychotics have a lower risk for neurological movement disorders known as extrapyramidal symptoms, which are the most common side effects associated with FGAs. SGAs, however, are associated with a higher risk for metabolic side effects such as weight gain, increase in blood glucose and cholesterol levels.

Both FGAs and SGAs are effective for the treatment of schizophrenia’s positive symptoms such as hallucinations and delusions. However, there is no evidence that SGAs have more efficacy than FGAs in alleviating cognitive and negative symptoms such as apathy and social withdrawal.

Second generation antipsychotics may be administered as:

• Oral: Tablets, capsules, solutions, suspensions, or sublingual tablets (placed under the tongue)
• Transdermal: Skin patches
• Injections: Intramuscular or subcutaneous

Second generation antipsychotics are used to treat the following conditions:

FDA-approved:

• Schizophrenia
• Schizoaffective disorder
• Bipolar I disorder, mania, depression and mixed episodes
• Bipolar I disorder maintenance
• Major depressive disorder
• Autism
• Tourette syndrome (a nervous system disorder involving repetitive movements or unwanted sounds)
• Agitation associated with schizophrenia and bipolar I mania
• Parkinson disease psychosis

Off-label uses:

• Chemotherapy associated nausea or vomiting
• Stuttering
• Alcohol dependence
• Insomnia
• Psychosis or agitation related to Alzheimer’s dementia
• Posttraumatic stress disorder (PTSD)

Orphan designation:

• N-glycanase 1 (NGLY1) deficiency

Side effects of second generation antipsychotics may include the following:

• Weight gain
• Headache
• Lightheadedness
• Dizziness
• Vertigo
• Fatigue
• Asthenia (weakness)
• Somnolence (drowsiness)
• Lethargy
• Sedation
• Confusion
• Agitation
• Aggression
• Insomnia
• Anxiety
• Irritability
• Anger
• Depression
• Hallucinations
• Disturbed sleep and nightmares
• Delirium
• Altered mental status
• Amnesia (memory loss)
• Schizophrenia
• Obsessive-compulsive disorder symptoms
• Pathological gambling
• Panic attack
• Suicidal ideation and attempt
• Gait disturbances
• Falls and accidental injury
• Tremor
• Nausea
• Vomiting
• Constipation
• Dyspepsia (indigestion)
• Increased appetite
• Increase in waist circumference
• Abdominal pain or discomfort
• Anorexia (loss of appetite) and weight loss
• Gastroesophageal reflux disease (GERD)
• Gastritis
• Diarrhea
• Hyperglycemia (increased blood glucose levels)
• Increased HbA1c values
• Blood glucose fluctuation
• Diabetes mellitus
• Diabetic ketoacidosis
• Diabetic coma with ketoacidosis
• Hyperinsulinemia (increase in blood insulin levels)
• Hypertriglyceridemia (high triglycerides in the blood)
• Hypercholesterolemia (high cholesterol in the blood)
• Hyperprolactinemia (increase in blood prolactin levels)
• Elevated liver enzyme levels (ALT and AST))
• Elevated creatinine phosphokinase (CPK)
• Salivary gland swelling
• Hypersalivation (increased salivation/drooling)
• Hyperhidrosis (excessive sweating)
• Dehydration
• Excessive thirst
• Extrapyramidal symptoms, which are drug-induced movement disorders such as:
  • Akathisia
  • Dystonia
  • Dyskinesia
  • Akinesia
  • Muscle stiffness
  • Neuroleptic malignant syndrome (rare, life-threatening reaction)
  • Parkinsonism
  • Tardive dyskinesia
• Paresthesia (prickling sensation)
• Impaired coordination
• Masked facies (loss of facial expressions)
• Restless leg syndrome
• Abnormal EEG
• Seizure
• Status epilepticus (a medical emergency, when a seizure lasts longer than five minutes)
• Depressed level or loss of consciousness
• Autonomic instability (dysfunction of the autonomic nervous system)
• Tachycardia (rapid heartbeat)
• Bradycardia (slow heartbeat)
• Arrhythmia (irregular heartbeat)
• Palpitations
• Abnormal ECG (QT prolongation)
• Torsades de Pointes (irregular heart rhythm in which the ventricles beat faster and out of synchronization with the atria)
• Temporary bundle branch block (block in the electrical pathway to the heart)
• First degree atrioventricular (AV) block
• Mitral valve incompetence
• Angina pectoris (chest pain)
• Cardiomyopathy (heart muscle disease)
• Myocarditis (inflammation of heart muscle)
• Myocardial infarction (heart attack)
• Cardiac arrest
• Increased diastolic blood pressure
• Hypertension (high blood pressure)
• Pseudopheochromocytoma (severe paroxysmal hypertension)
• Hypotension (low blood pressure)
• Orthostatic hypotension (blood pressure drop when standing up from sitting or lying down)
• Syncope (fainting)
• Ischemic stroke
• Cerebrovascular disease
• Hyperpyrexia (fever)
• Hypothermia (drop in body temperature)
• Rhinitis (inflammation of the nasal passage)
• Nasopharyngitis (inflammation of nose and throat)
• Rhinorrhea (runny nose)
• Nasal congestion
• Epistaxis (nasal bleeding)
• Cough
• Upper/lower respiratory tract infections
• Pneumonia
• Aspiration
• Pleural effusion (fluid around lungs)
• Dyspnea (shortness of breath)
• Sleep apnea
• Oral paresthesia (tingling, prickling or burning sensation)
• Oral hypoesthesia (reduced sensation or numbness)
• Circumoral edema (swelling around the mouth)
• Glossodynia (burning pain in the tongue)
• Swollen tongue
• Tongue paralysis
• Xerostomia (dry mouth)
• Dysgeusia (taste disorder)
• Dysphagia (swallowing difficulties)
• Hiccups
• Oropharyngeal pain (mouth and throat pain)
• Choking due to oropharyngeal muscle dysfunction
• Toothache
• Facial edema
• Pitting edema
• Periorbital edema (swelling around the eyes)
• Blurred vision
• Visual disturbances
• Narrow angle glaucoma (a condition that damages the optic nerve)
• Accommodation disorder (difficulty in focusing the eyes)
• Oculogyric crisis (prolonged upward deviation of the eyes)
• Ocular hyperemia (redness of eyes)
• Conjunctivitis (inflammation of the conjunctiva, the membrane over the whites of the eye and inner surface of eyelids)
• Teary eyes
• Eye discharge and margin crusting
• Eye and eyelid swelling
• Dry eyes
• Reduced visual acuity
• Ear pain
• Tinnitus (ringing in ears)
• Dysarthria (speech disorder)
• Stuttering
• Enuresis (urinary incontinence)
• Nocturnal enuresis (bedwetting)
• Pollakiuria (frequent daytime urination)
• Urinary abnormalities
• Dysuria (painful urination)
• Acute interstitial nephritis (inflammation in the kidneys)
• Kidney failure
• Hyperuricemia (excessive uric acid in the blood)
• Hyponatremia (low sodium in the blood)
• Acute pancreatitis (inflammation of the pancreas)
• Colitis (inflammation of the colon)
• Polyserositis (inflammation of serous membranes that line internal cavities)
• Ileus (temporary lack of intestinal muscle contraction)
• Intestinal obstruction
• Colon ischemia (reduced blood supply to the colon)
• Fecaloma (impacted stool)
• Fecal incontinence
• Hepatotoxicity (toxicity to the liver)
• Hepatitis
• Hepatic steatosis (fatty liver)
• Liver scarring (fibrosis) and damage (necrosis and cirrhosis)
• Liver failure
• Musculoskeletal stiffness and pain
• Myoclonus (muscle spasms)
• Back pain
• Myalgia (muscle pain)
• Arthralgia (joint pain)
• Pain in extremities
• Myasthenic syndrome (group of conditions that cause muscle weakness)
• Rhabdomyolysis (breakdown of skeletal muscle cells)
• Application site reactions with transdermal patches
• Injection site reactions
• Oral ulcers, blisters and inflammation with sublingual administration
• Hypersensitivity reactions such as:
  • Rash
  • Urticaria (hives)
  • Pruritus (itching)
  • Alopecia (hair loss)
  • Erythema multiforme (round lesions like bullseye)
  • Skin pigmentation disorder
  • Exfoliative dermatitis (redness and peeling of the skin)
  • Photosensitivity
  • Angioedema (swelling in the tissue under the skin or mucous membranes)
  • Oropharyngeal spasm (mouth and throat spasm)
  • Laryngospasm (spasm of the larynx)
  • Generalized exanthematous pustulosis (pustular eruptions)
  • Stevens-Johnson syndrome (a rare medical emergency with flu-like symptoms and a painful rash)
  • Drug rash with eosinophilia and systemic symptoms (DRESS)
  • Toxic epidermal necrolysis (a severe skin condition with widespread redness, skin cell death and exfoliation which can lead to sepsis)
  • Anaphylaxis (severe allergic reaction)
• Drug-induced systemic lupus erythematosus (SLE), an autoimmune condition
• Vasculitis (inflammation of blood vessels)
• Leukocytoclastic vasculitis (small blood vessel inflammation)
• Blood disorders such as:
  • Leukopenia (low count of leukocytes)
  • Neutropenia (low count of neutrophils)
  • Agranulocytosis (low granulocytes, immune cells with granules)
  • Anemia (reduced red blood cell count)
  • Elevated erythrocyte sedimentation rate (ESR)
  • Elevated hemoglobin/hematocrit
  • Eosinophilia (high level of eosinophils, a type of immune cell)
  • Thrombocytopenia (decrease in platelet count)
  • Thrombocytosis (excessive platelets in the blood)
  • Thrombotic thrombocytopenic purpura (a rare disorder that causes blood clots to form in small blood vessels)
• Myelosuppression (bone marrow depression)
• Deep vein thrombosis/DVT (formation of blood clot in deep veins, usually in the legs)
• Pulmonary embolism
• Hemorrhage
• Infections
• Sepsis
• Hypothyroidism
• Pituitary adenoma (benign tumor in the pituitary gland)
• Amenorrhea (absence of menstruation)
• Dysmenorrhea (menstrual pain and cramps)
• Breast enlargement
• Breast pain
• Vaginal discharge
• Gynecomastia (breast tissue growth in males) in children
• Galactorrhea (abnormal milk production and leakage)
• Sexual dysfunction
• Priapism (persistent and painful erection)
• Erectile dysfunction
• Retrograde ejaculation
• Ejaculation failure
• Syndrome of inappropriate antidiuretic hormone secretion (SIADH, a disorder which causes water retention)
• Drug withdrawal effects
• Death

Information contained herein is not intended to cover all possible side effects, precautions, warnings, drug interactions, allergic reactions, or adverse effects. Check with your doctor or pharmacist to make sure these drugs do not cause any harm when you take them along with other medicines. Never stop taking your medication and never change your dose or frequency without consulting your doctor.

Generic and brand names of second generation antipsychotic drugs include:

• Abilify
• Abilify Maintena
• Abilify MyCite
• aripiprazole
• Aristada
• Aristada Initio
• asenapine
• asenapine transdermal
• cariprazine
• clozapine
• Clozaril
• Fanapt
• Geodon
• iloperidone
• Invega
• Invega Sustenna
• Invega Trinza
• Latuda
• lurasidone
• Lybalvi
• Nuplazid
• olanzapine
• olanzapine/samidorphan
• paliperidone
• Perseris
• pimavanserin
• quetiapine
• Risperdal
• Risperdal Consta
• risperidone
• Saphris
• Secuado
• Seroquel
• Seroquel XR
• Versacloz
• Vraylar
• ziprasidone
• Zyprexa
• Zyprexa Relprevv
• Zyprexa Zydis