neuro/psych: schizophrenia and psychosis

symptoms of schizophrenia

• during the active stage:

  • unusual or extremely showed movements

  • incoherent or disorganized speaking (“word salad”)

  • hallucinations, usually related to hearing voices, or strange sounds

  • delusions: false beliefs that remain unchanged despite contradicting evidence

  • isolating behavior

  • emotionless facial expressions or speech

• others:

  • feeling suspicious, paranoid, or afraid frequently

  • not caring about their hygiene and appearance

  • depression, anxiety, and suicidal thoughts

  • using alcohol, nicotine, prescription medications, or recreational drugs to “self-medicate” their symptoms

positive symptoms of schizophrenia

• delusions → fixed, false beliefs generally outside of cultural or societal norms

• hallucinations → sensory perception with no basis in external stimulation (olfactory, tactile, gustatory, audible)

• disorganized speech → frequent derailment or loose associations (constantly moving from one topic to another), incoherence, or repetition of words

  • however, they think that their speech pattern is logical

• grossly disorganized or catatonic behavior → ranges from silliness to catatonia to purposeless movement to agitation

  • they also may not react to their environment appropriately

• these symptoms are very overt and easily picked up by a stranger, for example

negative symptoms of schizophrenia

• the 5 “As” of schizophrenia

• blunted affect → emotional blunting or difficulty expressing emotion facially

• alogia → inability to speak or “poverty of speech”

  • eg. giving one word answers, lack of spontaneous speech, or speech that is vague and lacks a lot of details

• avolition → lack of desire or motivation to pursue self-initiated goals

  • for this reason, many patients are unemployed

• anhedonia → inability to experience pleasurable emotions

• asociality → inability or unwillingness to participate in normal social situations

• mood symptoms → depression, dysphoria, hopelessness, and demoralization (loss of confidence)

• social and occupational dysfunction → inability to maintain employment, homelessness, or lack or close friendships

• other cognitive symptoms such as difficulty in maintaining or shifting attention, deficits in working memory and long-term declarative memory, deficits in executive function, deficits in skill acquisition, and deficits in social cognition

  • these may be primary (disease-related), or secondary (caused by medications, depressions, EPS, etc)

• these symptoms may be a little more difficult “sus out”

diagnostic criteria for schizophrenia

• at least 2 symptoms must be present for a significant percent of time for at least a one-month period or more (less if treated)

• at least one of the symptoms must be delusions, hallucinations, or disorganized speech

  • other symptoms include grossly disorganized or catatonic behavior and negative symptoms

• one or more areas of function (eg. work, social, personal, etc) must be markedly below the previous level for a significant portion of time, evidenced by social isolation, difficulty maintaining employment or employment below educational level, impaired self-care, or impaired or diminished family or social relationships

• duration of at least six months, including at least one month of symptoms (unless successfully treated) as noted above

• does not better meet criteria for schizoaffective or mood disorders

• origin of symptoms are not solely due to a substance and/or a general medical condition

• prominent hallucinations or delusions must be present for at least one month if there is a history of autism spectrum disorder

law of thirds

• 1/3 of patients will experience significant treatment effects and will respond well to pharmacologic interventions

• 1/3 of patients will see significant improvement, but not to the same degree as above → they may have relapses, hospitalizations, or difficulties with employment or social areas

• 1/3 of patients will have significant symptoms and will only respond mildly to treatment → they might require institutionalization, group homes, or other forms of assistance

  • 10% of these patients will be “treatment resistant” → institutionalized at state hospitals

dopamine hypothesis of schizophrenia 

• schizophrenia arises from monoamine dysfunction, especially at dopamine pathways:

  • excessive dopamine activity in the mesolimbic pathway (hyperdopaminergic)

    • D2 receptor activation (due to hyperactive NMDA receptors) in the nucleus accumbens projected from the ventral tegmental area (VTA)

    • this activation causes the positive symptoms that we see!

  • dopamine deficiency in the meso-cortical pathway (hypodopaminergic)

    • decreased dopamine activity from the VT to the dorsolateral pre-frontal cortex

    • this deficiency causes the negative symptoms that we see!

• this is considered the major and most influential hypothesis for schizophrenia 

D1-like receptors

• D1 and D5

• Gs-coupled → ↑ cAMP → excitatory

  • activation enhancing NMDA receptor conductance → increased glutamate signaling

• so, activation of these receptors strengthens excitatory cortical circuits (pre-frontal cortex), particularly those involved in working memory, attention, and executive function

D2-like receptors

• D2, D3, D4

• Gi-coupled → ↓ cAMP → inhibitory

  • overall effect: ↓ neurotransmitter release and neuronal firing (inhibits neuronal excitability)

• these receptors are notably responsible for inhibiting GABAergic neurons 

  • GABA is responsible for inhibiting excessive excitatory activity, so when GABA release is inhibited (disinhibition), we see unleashed excessive excitatory activity → positive psychotic symptoms!

  • this is why antagonizing these receptors can reduce positive symptomolgy

glutamate hypothesis of schizophrenia

• proposes that in schizophrenia, there is NMDA receptor hypofunction (especially on GABAergic interneurons)

• this leads to excess glutamate and dopamine dysregulation downstream

  • a hyperglutamic state can lead to excitotoxicity

• it explains why NMDA antagonists (PCP, ketamine) can produce both positive and negative schizophrenia-like symptoms

• so, glutamatergic dysfunction likely interacts with dopamine abnormalities

serotonin hypothesis of schizophrenia

• 5HT-2A receptor inhibition (antagonism) causes the release of dopamine in certain areas of the brain

  • in more fancy words: 5HT-2A blockade enhances dopamine release in mesocortical and nigrostriatal tracts via disinhibition of dopaminergic neurons in the ventral tegmental area (VTA)

  • in the mesocortical pathway → improved cognition and a decrease in negative symptoms

  • in the nigrostriatal pathway → decreased EPS

  • this is also why antipsychotics that block 5HT-2A also block the effects of drugs such as LSD or cocaine (which are 5HT-2A agonists)!

• atypical antipsychotics (like clozapine, risperidone) block 5HT-2A and D2, improving both positive and negative symptoms, highlighting serotonin’s modulatory role on dopamine systems

• serotonin modulates not only dopaminergic neurons, but also glutamatergic and GABAergic neurotransmission as well!

treatment goals for schizophrenia

• prevent corrosion of social functioning within the first 5-12 years

  • after the first symptoms in late adolescence-early adulthood, patients are more responsive to the first antipsychotic they receive (and thus are more likely to have ADEs or EPS)

  • but, aggressively treating this first episode can beneficially impact the trajectory of their disease

    • for some people, if they get started on medications early enough, there’s some damage that occurs due to that hyper stimulation and inflammatory damage that occurs from these neurons that are firing all of the time, and if you can salvage that, the rest of the surrounding area can begin to heal and it can recover function of the negative symptoms

    • but, if the patient spends a lot of time in psychosis, their brain suffers more damage

• improve quality of life

• target symptoms appropriately and realistically

• minimize adverse effects

• combination of medication, supportive care, psychosocial therapies, financial support, and vocational support is needed for overall improvement

good prognosis of schizophrenia

• late onset

• precipitating factors that may cause psychosis → eg. major life stressor, losing a job, etc

• good premorbid function → good level of cognitive and social performance before the onset of schizophrenia

• mood disorder symptoms

• married

• family history of mood disorder

• good support system

• positive symptoms predominate their disease state → most antipsychotics target positive symptoms pretty well

poor prognosis of schizophrenia

• young onset

• no precipitating factors that may cause psychosis

• poor premorbid function → poor level of cognitive and social performance before the onset of schizophrenia

• mostly negative symptoms

• single, divorced, or widowed

• no children

• family history of schizophrenia

• neurological signs and symptoms

• perinatal trauma

• homeless

non-pharmacological options for schizophrenia

• psychosocial therapies

  • social skills training

  • family-oriented therapies

  • assertive community treatments

  • group therapy

  • art therapy

  • cognitive behavioral therapy

• electroconvulsive therapy (ECT)

pharmacological options for schizophrenia 

• typical antipsychotics (aka first generation antipsychotics or FGAs)

  • conventional, traditional therapeutics

• atypical antipsychotics (aka second generation antipsychotics or SGAs)

  • “novel” therapeutics

treatment guidelines for schizophrenia

• the vast majority view FGA and SGA as first- and second-line therapies, while clozapine tends to be reserved for third-line therapy

  • fourth line is always using clozapine as an augmenting medication

how to choose treatment for schizophrenia

• besides using the guidelines, it also depends on…

  • patient history

  • types of presenting symptoms

  • short-term and long-term efficacy profiles of the various agents

  • side effect profile of the agents

  • cost of the treatment to the patient and the healthcare system (as well as hospital stay or other interventions)

• for example, if a patient rolls in excessively psychotic and hallucinating, it would be appropriate to give haloperidol or a higher dose of an antipsychotic

  • essentially we are trying to tranquillize them

side effects of H1 antagonism

• sedation

• weight gain

side effects of alpha-1 antagonism

• orthostasis

side effects of alpha-2 antagonism

• antihypertensive blockade

side effects D2 antagonism

• EPS

• increased prolactin

side effects of 5HT-2C antagonism

• weight gain

• seizures

treatment expectations for schizophrenia

• within 1-2 days…

  • treatment improves symptoms such as agitation, hyperactivity, combativeness, and hostility

• within 1-2 weeks…

  • treatment improves hallucinations, sleep, appetite, hygiene, social skills, and some delusions

• within 1-2 months…

  • treatment improves delusions, judgement, insight, and abstract thinking

treatment response

• decrease in positive/negative symptoms by 20-50% over a 4 week period, evident by BPRS/PANSS scores

partial treatment response

• partial decrease in positive/negative symptoms over a 12 week period

no treatment response

• no decrease in positive/negative symptoms over a 3-4 week period

assessing treatment response in schizophrenia 

• brief psychiatric rating scale (BPRS)

  • clinician rated, 24 item, 7 point scale

• positive and negative syndrome scale (PANSS)

  • clinician rated, 30 item, 7 point scale

  • 25% decrease in symptoms = response for refractory patients

  • 50% decrease in symptoms = response for acute, symptomatic patients

• clinical and global impression’s scale (CGI)

  • observational, 7 point rating scale

  • remission → low score for at least 3 months on this scale

considerations for ALL antipsychotics

• administration reduces all-cause mortality

  • this include mortality from suicide, as well as mortality from natural causes

  • sometimes, we may neglect other causes of mortality or other comorbidities, and only focus on the psychological aspect

first-line treatment for treatment-naive patients

• risperidone

• aripiprazole

• ziprasidone

MOA of typical antipsychotics

• pure blockade of D2 receptors in the mesolimbic pathway, reducing dopamine hyperactivity from the VTA and thus reducing positive symptoms

  • just to be clear, these antipsychotics block ALL dopaminergic neurons, not just neurons in the mesolimbic pathway

  • this can actually worsen negative and cognitive symptoms, since they’re also decreasing dopamine in the already deficient mesocortical pathway → recall the dopamine hypothesis

  • this is why they also cause more side effects such as increased EPS in the nigrostriatal pathway, and higher levels of prolactin in the tuberoinfundibulnar pathway!

typical antipsychotics (1st gen. antipsychotics) → drugs

• chlorpromazine

• trifluoperazine

• perphenazine

• thioridazine

• fluphenazine

• thiothixene

• haloperidol

• mesoridazine

• loxapine

• molindone

brand name for chlorpromazine

• brand name

  • Thorazine

brand name for trifluoperazine

• brand name

  • Stelazine

brand name for perphenazine

• brand name

  • Trilafon

brand name for thioridazine

• brand name

  • Mellaril

brand name for fluphenazine

• brand name

  • Prolixin

brand name for thiothixene

• brand name

  • Navane

brand name for haloperidol

• brand name

  • Haldol

brand name for mesoridazine

• brand name

  • Serentil

brand name for loxapine

• brand name

  • Loxitane

brand name for molindone

• brand name

  • Moban

high potency typical antipsychotics → drugs

• fluphenazine

• haloperidol

mid-potency typical antipsychotics → drugs

• thiothixene 4 mg

• trifluoperazine 5 mg

• perphenazine 8 mg

• loxapine 2 mg

• molindone 2 mg

low potency typical antipsychotics

• mesoridazine 50 mg

• thioridazine 100 mg

• chlorpromazine 100 mg

importance of high potency typical antipsychotics

• these antipsychotics have the highest risk of EPS, which is why only low doses are used (2 mg)

  • they have D2 receptor antagonism, but they also block M1, H1, and sigma-1, causing more anti-cholinergic ADEs

importance of low potency typical antipsychotics

• these antipsychotics have the lowest risk of EPS, which is why higher doses may be used

  • on the downside, these drugs have increased alpha-1 and cholinergic antagonism → side effects such as orthostasis and other anti-cholinergic effects

side effects of typical antipsychotics

• extrapyramidal symptoms (EPS)

• anticholinergic effects

• cardiovascular

• endocrine

• central/autonomic nervous system

• hematological

• dermatological

extrapyramidal symptoms (EPS)

• caused by too little dopamine, particularly in the nigrostriatal pathway in the brain

• acute symptoms:

  • dystonia

  • akathisia

  • pseudoparkinsonism

• chronic symptoms:

  • tardive dyskinesia

• emergency:

  • neuroleptic malignant syndrome (NMS)

dystonia

• sustained, uncontrollable muscular contraction, especially of the laryngeal muscles

  • fast onset: 24-96 hours of initial dose or dose change

• you may also see patients with their eyes rolled back

• risk factors:

  • younger males

  • use of high potency agents (especially high doses)

treatment for dystonia

• a combination of…

  • anticholinergics (IM/IV) → diphenhydramine 50 mg, benztropine 2 mg

    • give anticholinergics for at least a few days after until the rest of the antipsychotic is cleared from the body

  • benzodiazepines → lorazepam 2 mg IM, diazepam 5-10 mg IV push

pseudoparkinsonism

• 4 cardinal signs:

  • hypertonia → too much muscle tone leading to leading to stiffness, rigidity, and difficulty with movement

  • abnormal gait → stooped posture, shuffling

  • bradykinesia or akinesia → loss, slowing, or impairment of the power of voluntary movement

  • resting tremor

• generally appears in the first 1-3 months of treatment

  • 30% of chronic patients

• risk factors:

  • increased age

  • high doses

  • history of pseudoparkinsonism

  • history of basal ganglia injury

treatment for pseudoparkinsonism

• options:

  • decrease the dose

  • add a preventative drug

  • switch the drug

• preventative drugs include anticholinergics/antihistamines:

  • benztropine (Cogentin) 1-6 mg daily

  • biperiden (Akineton) 2-16 mg daily

  • procyclidine (Kemadrin) 5-30 mg daily

  • trihexyphenidyl (Artane) 5-15 mg daily

  • diphenhydramine (Benadryl) 50-300 mg daily

  • amantadine (Symmetrel) 100-400 mg daily

    • amantadine is actually a dopamine reuptake inhibitor → last line due to pro-dopaminergic effects which can worsen positive symptoms

• symptoms usually resolve within 3-4 days after treatment

akathisia

• internal and motor restlessness

  • pacing, shuffling, or tapping feet

  • “I just can’t sit still!”

• risk factors:

  • using high potency typicals

  • use of SSRIs

treatment for akathisia

• benzodiazepines:

  • lorazepam (Ativan) 1-8 mg daily

  • clonazepam (Klonopin) 0.5-6 mg daily

• beta blockers:

  • propranolol (Inderal) 30-120 mg daily

  • metoprolol (Lopressor) 50-400 mg daily

• use anticholinergics only if concomitant Parkinsonism is present

tardive dyskinesia

• late-onset of abnormal involuntary movements

  • associated with prolonged antipsychotic use

• oral-buccal: primarily involves a combination of tongue twisting/protrusion, lip smacking, mouth puckering, and lateral jaw movements in a stereotypic manner (eg. frequent, repetitive, and often purposeless movements)

  • may also see rhythmic movements on other parts of the body, such as feet curling, trunk rocking, etc

• there is a 20% rate among patients receiving typicals

  • 5% increased risk with each year of use

  • 5% chance in newly diagnosed schizophrenia 

  • 8% of cases are irreversible

• risk factors:

  • increased age

  • female gender

  • chronic use of antipsychotics

etiology of tardive dyskinesia

1. blockade of D2 receptors in the nigrostriatal dopamine pathway causes them to upregulate (increased amounts of dopamine receptors)

2. this upregulation may cause this symptom as dopamine now has a higher likelihood of binding to the increased amount of D2 receptors

3. however, since it causes upregulation of dopamine receptors, you could also INCREASE the dose of the dopamine antagonist (antipsychotic) to block more dopamine receptors and improve symptoms!

   1. or just give therapies that decrease dopamine (VMAT inhibitors)

treatment for tardive dyskinesia

• pharmacotherapy

  • vitamin E 1600 IU daily → free radical scavenger

  • valbenazine (Ingrezza) 40-80 mg daily → VMAT inhibitor

  • deutetrabenazine (Austeodo XR) 12-48 mg daily → VMAT inhibitor

• prevention:

  • AIM scale

  • monitoring for symptoms

    • signs? → switch to an atypical antipsychotic

atypical antipsychotics LEAST likely to cause tardive dyskinesia

• clozapine

• quetiapine

MOA of VMAT inhibitors

• block the transport of monoamine neurotransmitters (such as dopamine) into synaptic vesicles

  • this inhibition leads to a decrease in the amount of neurotransmitter available for release, resulting in reduced neurotransmission and allows for continued degradation of dopamine within the synapse

VMAT inhibitors → drugs

• FDA approved for tardive dyskinesia:

  • duetrabenazine

  • valbenazine

• off-label for tardive dyskinesia:

  • tetrabenazine

considerations for VMAT inhibitors

• side effects may include Parkinsonism or depression

• super expensive

neuroleptic malignant syndrome (NMS)

• considered a psychiatric emergency → occurs with 0.5-1% of patients of typicals or patients that are exposed to dopamine antagonists

• onset is delayed → 1-2 weeks after initiation or after a dose increase

• diagnostic criteria:

  • severe muscle rigidity and increase in temperature associated with antipsychotic usage

  • requires ≥2 of the following symptoms:

    • diaphoresis, dysphagia, tremor, incontinence, change in consciousness, mutism, increased BP, leucocytosis, increase in CPK/urinary myoglobin

    • these symptoms are NOT due to another substance, a neurological, or other general medical condition

• risk factors:

  • higher doses of antipsychotics

  • dehydration!!!

  • using multiple antipsychotics at the same time

common signs of NMS

• “can't Bend(er)” → imagine a steel robot on fire

  • mental status changes

  • lead pipe rigidity → can’t bend ‘er limbs

  • autonomic instability → high BP

  • sweating

  • high fever

treatment for moderate NMS

• clinical presentation:

  • moderate rigidity

  • confusion or catatonia, increased temp (38-40 C)

  • HR 100-120 bpm

• supportive care measures:

  • discontinue the antipsychotic(s)

  • manage fluids

  • cooling measures (cooling blanket)

  • correct risk factors

  • ICU

• first-line treatment

  • lorazepam 1-2 mg IM/IV q4-6h

  • bromocriptine 2.5-5 mg po/NG q8h → increase in dopamine

  • amantadine 100 mg po q8h → increase in dopamine

• you should NEVER rechallenge patients with another antipsychotic if they experience this!

treatment for severe NMS

• clinical presentation:

  • severe rigidity → look out for muscle breakdown

  • catatonia or coma

  • temperature ≥ 40C

  • HR ≥ 120

• supportive measures:

  • discontinue the antipsychotic(s)

  • manage fluids

  • cooling measures (cooling blanket)

  • correct risk factors

  • ICU

• first-line treatment:

  • dantrolene 1-2.5 mg IV q6h for 48 hours → skeletal muscle relaxant

  • bromocriptine 2.5-5 mg po/NG q8h

  • amantadine 100 mg po q8h

• you should NEVER rechallenge patients with another antipsychotic if they experience this!

endocrine effects of typical antipsychotics

• weight gain

  • higher risk with lower potency agents or atypicals

• hyperprolactinemia

  • due to D2 blockade in the tuberofindublar pathway → less inhibition on prolactin

  • common signs:

    • galactorrhea

    • gynecomastia

    • sexual dysfunction

    • changes in menstruation

  • long-term effects:

    • osteoporosis

    • infertility

    • CVD

    • breast cancer..?

cardiovascular effects of typical antipsychotics

• orthostatic hypotension

  • due to alpha-1 blockade

• QT prolongation

  • this is a class effect for ALL antipsychotics

  • BBW for thioridazine and mesoridazine

  • contraindicated if patient has a QTc interval > 500 ms

  • baseline EKG and monitor electrolytes (Mg++ and K+)

CNS effects of typical antipsychotics

• due to their antihistamine and anticholinergic effects, they may impair patients’ cognitive function

  • may want to consider the fact that you are giving these drugs to a patient that is already cognitively impaired in some way → this could be problematic

• seizures are also a class effect for ALL antipsychotics

  • increased risk with aliphatic phenothiazines (chlorpromazine)

  • decreased risk with molindone

hematological effects of typical antipsychotics

• blood abnormalities (dyscrasias)

considerations for chlorpromazine

• can cause:

  • choleostatic jaundice

  • corneal deposits

  • increased photosensitivity (increased risk of hyperthermia and blue/grey discoloration)

considerations for thioridazine

• can cause:

  • pigmentary retinopathy

dosing for chlorpromazine

• starting dose:

  • 10-25 mg TID

• maintenance dose:

  • 100-800 mg daily

• maximum dose:

  • 2 grams daily

dosing for thioridazine

• starting dose:

  • 50-100 mg TID

• maintenance dose:

  • 100-800 mg daily

• maximum dose:

  • 800 mg daily

dosing for perphenazine

• starting dose:

  • 4-8 mg TID

• maintenance dose:

  • 12-64 mg daily

• maximum dose:

  • 64 mg daily

dosing for fluphenazine

• starting dose:

  • 0.5-10 mg daily

• maintenance dose:

  • 2-20 mg daily

• maximum dose:

  • 40 mg daily

dosing for haloperidol

• starting dose:

  • 1-15 mg daily

• maintenance dose:

  • 2-20 mg daily

• maximum dose:

  • 100 mg daily

advantages for long-acting injectable antipsychotics (LAIs)

• generally considered for patients who:

  • prefer this route of administration

  • have problems with medication adherence → dosing every 2-4 weeks

• can decrease suicide rates

  • eliminates risk of suicide with overdosing

• provides a more simple medication regimen

• regular contact with the healthcare system

• predictable bioavailability

  • avoids first-pass metabolism

  • more predictable and stable plasma levels with less peaks than oral route

• useful in distinguishing between poor adherence vs poor response

• provides the ability to track non-adherence

• long-term maintenance medication can prevent relapse

• for the most part, patients should start with an oral formulation first to establish tolerability → with these agents, it may be harder to manage if not tolerable

disadvantages of long-acting antipsychotics (LAIs)

• difficult to manage ADEs due to inability to withdraw medication

  • these formulations have a longer half-life → once injected, you can’t “take it back”

  • can increase the risk of EPS

• not the best for patients with fear of injection and discomfort

• may be a delay in achieving therapeutic concentration (Css)

• pain at injection site

• cost → especially 2nd generation antipsychotics

typical antipsychotics that have long-acting injectable formulations

• fluphenazine

• haloperidol

place in therapy for typical antipsychotics

• considered 2nd or 3rd line agents for newly diagnosed patients

  • can SOMETIMES be combined with 2nd gen antipsychotics

• some guidelines may allow for first-line therapy

• overall, with therapy on these medications, patients are well-managed, there are long-acting formulations available for compliance, and they’re pretty affordable 

  • the only potential downside is the EPS

MOA of atypical antipsychotics

• dual blockade (antagonism) of both 5HT-2A and D2 receptors

  • the dopamine inhibition targets the positive symptoms patients experience

    • reduction in positive symptoms secondary to D2 blockade in the mesolimbic pathway

  • the serotonergic inhibition, on the other hand, alleviates some of the negative symptoms patients may experience by increasing dopamine release, setting them apart!

    • improvement in negative symptoms like affect or cognition secondary to 5HT-2A antagonism (or inverse agonism) in the mesocortical pathway

    • 5HT-2A receptors are inhibitory on dopaminergic neurons → blocking these receptors results in increased dopamine release in certain pathways, particularly the mesocortical and nigrostriatal tracts 

  • another aspect of this 5HT-2A blockade in the nigrostriatal pathway is the counterbalance of dopamine inhibition

    • recall that dopamine inhibition at the nigrostriatal pathway can lead to EPS (motor side effects), so 5HT-2A blockade and the subsequent increase in dopamine here is what can actually help prevent these EPS!

    • so, 5HT-2A blockade allows just enough dopamine release to offset D2 antagonism in those other pathways, improving both EPS and negative symptoms at the same time

• all this to say that these medications are more like dopamine modulators rather than pure dopamine blockers due to their dual pharmacology

considerations for atypical antipsychotics

• can see improvement in movement-related ADEs generally seen with first generation drugs

  • decreased risk of EPS at effective antipsychotic doses

• we can also see an improvement in negative and cognitive symptoms as well!

• no difference in efficacy when compared to typicals (with a few exceptions)

• however, these antipsychotics have an increased risk of metabolic concerns:

  • weight gain

  • dyslipidemia

  • increase in blood glucose

atypical antipsychotics (2nd gen. antipsychotics) → drugs

• clozapine

• olanzapine

• risperidone

• quetiapine

• ziprasidone

• aripiprazole

• paliperidone

• asenapine

• iloperidone

• lurasidone

• brexpiprazole

• cariprazine

• lumateperone

brand name for clozapine

• brand name

  • Clozaril

  • Fazaclo

  • Versacloz

  • Clopine

brand name for olanzapine

• brand name

  • Zyprexa

  • Zydis (SL)

  • Relprevv (IM)

brand name for risperidone

• brand name

  • Risperdal

  • Consta (IM)

  • Perseris (SC)

  • Rykindo (IM)

  • Uzedy (SC)

brand name for quetiapine

• brand name

  • Seroquel

brand name for ziprasidone

• brand name

  • Geodon

brand name for aripiprazole

• brand name

  • Ambilify

  • Discmelt (SL)

  • Maintena (IM)

  • Aristada (IM)

  • Mycite

  • Asimtufii (IM)

brand name for paliperidone

• brand name

  • Invega

  • Sustenna (IM)

  • Trinza (IM)

  • Hafyera (IM)

brand name for asenapine

• brand name

  • Saphris

  • Secuado (TD)

brand name for iloperidone

• brand name

  • Fanapt

brand name for lurasidone

• brand name

  • Latuda

brand name for brexpiprazole

• brand name

  • Rexulti

brand name for cariprazine

• brand name

  • Vraylar

brand name for lumateperone

• brand name

  • Caplyta

atypical antipsychotics that are D2 partial agonists (NOT D2 antagonists) → drugs

• aripiprazole

• brexpiprazole

• cariprazine

significance of partial agonism at the D2 receptor

• these drugs mechanistically work by binding to the D2 receptor and activating it, but less strongly than the full agonist (dopamine) → recall the dopamine hypothesis

• if dopamine levels are high, the drug competes for receptor binding, reducing overall activation → net dopamine decrease, acting as an antagonist

  • recall that the mesolimbic and striatal area has high dopamine (moderate reduction of positive sxs)

• if dopamine levels are low, the drug provides some activation → net dopamine increase, acting as an agonist

  • recall that the mesocortical area has low dopamine (improves negative sxs)

• because of this, these drugs are slightly weaker on positive symptoms but provider better tolerability and broader control across pathways

  • you wouldn’t necessarily give these to patients with severe psychosis due to limited potency compared to D2 antagonists

  • however, these drugs are great for decreased EPS and hyperprolactinemia risk, and they may also improve negative symptoms due to activation of D2 receptors!

• in all, these drugs “occupy” the receptor and blunt excessive dopamine signaling, but still provide a low-level baseline signal when dopamine is deficient

receptor occupancy

• refers to the percentage of receptors occupied by medication (dopamine antagonists) on the post-synaptic neuron

• for treatment of schizophrenia, clinicians aim for a therapeutic window of 60-80% occupancy

  • > 80% → more EPS

  • < 60% → no therapeutic dosing (ineffective)

side effects of D2 partial agonists

• low to no QT prolongation

• low risk of sedation

• no anti-cholinergic effects

• akathisia (restlessness)

• GI upset