Atypical & Typical Antipsychotics Flashcards
Identify major First Generation/Typicals (FGA) drugs
Apply the pharmacological concepts underlying the use of FGAs
Describe the mechanism of action of how the various FGAs work
Examine how FGAs act upon, amplify, and modify neural functions, ultimately affecting mood and behavior
Analyze the use of FGAs in clinical practice, including combination or augmentation strategies.
Understand the art of psychopharmacology including potential advantages, disadvantages and primary target symptoms of various FGAs.
Discuss precautions, contraindications, and implications of FGAs use in special populations including those with hepatic, renal or cardiac impairment, elderly, children and adolescents, pregnancy and lactation.
Identify major Second Generation/Atypicals (SGA) drugs.
Apply the pharmacological concepts underlying the use of SGAs
Describe the mechanism of action of how the various SGAs work.
Examine how SGAs act upon, amplify, and modify neural functions, ultimately affecting mood and behavior.
Analyze the use of SGAs in clinical practice, including combination or augmentation strategies.
Understand the art of psychopharmacology including potential advantages, disadvantages and primary target symptoms of various SGAs.
Meaning of Neuroleptic/ Conventional Antipsychotics/ Typical antipsychotics
The term used for 1st generation antipsychotics because of their ability to produce neurolepsis
Meaning of Neurolepsis
Psychomotor slowing, Emotional quieting, Affective indifference
Meaning of Atypical antipsychotic/ second-generation antipsychotics
Lower risk extrapyramidal symptoms, Efficacy against cognitive and negative symptoms, Lack of prolactin elevation, Efficacy for treatment-resistant patients
Atypical Antipsychotics/ Second Generation antipsychotics
Serotonin-dopamine antaganist
Third generation antipsychotics
Dopamine partial agonist (Aripiprazole is the only FDA approved)
First Generation Antipsychotics (FGAs) adverse effects
Higher risk of Neurological side effects
Second Generation Antipsychotics (SGAs) adverse effects
Lower risk of neurological side effects
Higher risk of metabolic side effects - Weight gain, DM, obesity,
First Generation Antipsychotics notes
Are D2 antagonists (remember D2R = detour from reality)
Are associated with higher risk of extrapyramidal sx (EPS)
Second Generational Antipsychotics notes
Are 5HT2A/D2 antagonsits
Lower risk EPS
Higher risk of Metabolic sx
DOPAMINE Mnemonic related to FGAs blocked
Drive - “slow but not sleepy”, clumsy
psychOsis - hallucinations and delusions
Parkinsonism - PArkinson’s Disease = doPAmine Down
Attention - “difficult for me to explain”, want to finish as soon as possible
Motor -
Inhibition of prolactin
Narcotics
Extrapyramidal - involuntary motor tracks,
Extrapyramidal Side Effects
Acute Dystonia - “muscle” contraction - 4 hours
Akathisia - “Rustle” restlessness, jittery - 4 Days
Akinesia - “Hustle” shuffle/inability to move - 4 Weeks
Tardive Dyskinisa
Hyperprolactinemia - increased breast size - RISE-PAIRidone gives RISE to a PAIR
Neuroleptic Malignant Syndrome - Confusion, Agitation, Hyperthermia (>105 F), Muscular Ridgity, Seizures + Recent Antipsychotic use = NMS!
Tardive Dyskinesia
Extrapyramidal side effect
Can be IRREVERSIBLE
Constant involuntary periorbital muscles
CHEWING TARdive
Treated with Benadryl
Neuroleptic Malignant Syndrome Sx & Tx
Confusion, Agitation, Hyperthermia (>105 F), Muscular Ridgity, Seizures + Recent Antipsychotic use = NMS!
Tx w/ Dantrolene (hint DANtrolene Never Missed a Step)
dosing form note to remember
PO before DEPOT
PO to confirm they can tolerate the med b4 giving the med as a Depot IM injection that will be in place and affecting the pt for weeks
Chlorpromazine/ Thorazine
FGAs
Affects DA-, Ach-, NE-, His-
Wide Side Effect Profile
Sediment Deposits in Cornea - (hint CHLOR-neal Deposits)
Thoridazine/ Mellaril
FGAs
Affects DA-, ACH-
Side effect - retinal deposits (Thioridazine= reTinal deposits
Haloperidol/ Haldol
FGAs
Affects DA- (more D2 receptor-specific)
HOLDol
Less anticholinergic, Antihystamic, and Antinoredergic affects
Higher rate of extrapyramidal side effects
Depot formula is the Decanoate = DECAde
Clozapine/ Clozaril
SGAs
affects DA- & SE partial agonist
Most effective agent against schizophrenia
The deadly side effect of agranulocytosis (the loss of all WBC)
- watch it CLOZely for agranulocytosis
never 1st line
Must be registered and the ANC checked prior and serial ANC throughout the 1st year
D/C immediately if ANC falls below 1500
Olanzapine/ Zyprexa
SGAs
DA- SE+
Second only to clozapine in efficacy but without the side effect of agranulocytosis
IS a 1st line treatment for schizophrenia
Highest of all prescribed but also the worst for weight gain without increased caloric intake
Think Olanzapine and an Obesie person
O for Obesity
Risperidone/ Risperdal
SGAs
DA- SE- NE- His-
RISe & Shine (less sedation)
RISe to a Pair
Low EPS sx
High Metabolic syndrome
High relation to Gynocomystomy
Quetiapine/ Seroquel
SGAs
DA- SE- NE- HIS-
Low EPS sx
High Metabolic syndrome
Quetiapine = Quiet time (increased sedation)
Ziprasidone/ Geodon
SGAs
DA- SE- NE- HIS-
Low EPS sx
High Metabolic syndrome
Prolongs QT interval
Geodon think GEOmetro a Zippy Car (reminding u to do an EKG
Aripiprazole/ Abilify
Third Generation As
DA partial agonist, SE partial agonist
Helps with maintenance therapy not acute psychosis
Think And Abilify for dopamine and serotonin
Antidepressant AND Abilify for refractory cases of MDD
Description of Psychosis
Psychosis is a syndrome, a mixture of symptoms that can be associated with many different psychiatric disorders but is not a specific disorder itself in DSM or ICD diagnostic criteria.
Symptoms of Psychosis
At a minimum, delusions and hallucinations and generally includes symptoms such as disorganized speech, disorganized behavior, and gross distortions of reality.
Types of Psychosis
Paranoid Psychosis - Paranoid Projections; Hostile Belligerence & Grandiose Expansiveness
Disorganized/Excited Psychosis - Conceptual Disorganization, Disorientation, Excitement
Depressive Psychosis - Psychomotor retardation & Apathy; Anxious Self-Punishment & Blame
Paranoid Psychosis -
Paranoid Projections; Hostile Belligerence & Grandiose Expansiveness
Disorganized/Excited Psychosis -
Conceptual Disorganization, Disorientation, Excitement
Schizophrenia consists of
a mixture of symptoms that are commonly divided into two major categories: Positive and Negative symptoms
Schizophrenias Positive symptoms are
Delusion and hallucinations, reflect the development of the symptoms of psychosis; they can be dramatic and may reflect a loss of touch with reality.
Schizophrenia Negative symptoms will
Reflect the loss of normal functions and feelings, such as losing interest in things and not being able to experience pleasure. Think alogia, affective blunting or flattening, asociality, anhedonia, avolition & attentional impairment.
Alogia
The poverty of speech, (talks little, uses few words)
Dysfunction of Communication
Neg Sx of Schizophrenia
Affective blunting
Reduced range of emotions (perception, experience, and expression) ex - feels numb or empty inside, recalls few emotional experiences, good or bad
Dysfunction of Affect
Neg Sx of Schizophrenia
Asociality
Reduced social drive and interactions ( little sexual interest, few friends, little interest in spending time with (or little time spent with) friends)
Dysfunction of socialization
Neg Sx of Schizophrenia
Anhedonia
Reduced ability to experience pleasure (finds previous hobbies or interests unpleasurable
Dysfunction of capacity for pleasure
Neg Sx of Schizophrenia
Avolition
Reduced desire, motivation, and persistence, (reduced ability to undertake and complete everyday tasks, may have poor personal hygiene)
Dysfunction of motivation
Neg Sx of Schizophrenia
Different symptom domains of schizophrenia are hypothesized to be regulated by unique brain regions:
Positive symptoms - mesolimbic
Negative symptoms - mesocortical/ prefrontal cortex
Cognitive sx - the dorsolateral prefrontal cortex
Aggressive sx - orbitofrontal cortex
Affective sx - the ventromedial prefrontal cortex
Five dopamine pathways in the brain
he mesolimbic dopamine pathway,
the mesocortical dopamine pathway,
the nigrostriatal dopamine pathway,
the tuberoinfundibular dopamine pathway, and
a fifth pathway that innervates the thalamus.
Mesolimbic dopamine pathway and positive symptoms of schizophrenia
The mesolimbic dopamine pathway projects from dopaminergic cell bodies in the ventral tegmental area of the brainstem to axon terminals in one of the limbic areas of the brain, namely the nucleus accumbens in the ventral striatum
This pathway is thought to have an important role in several emotional behaviors, including the positive symptoms of psychosis, motivation, pleasure, and reward.
It has long been observed that diseases or drugs that increase dopamine will enhance or produce positive psychotic symptoms, whereas drugs that decrease dopamine will decrease or stop positive symptoms. For example stimulant drugs such as amphetamine and cocaine release dopamine, and if given repetitively can cause a paranoid psychosis virtually indistinguishable from the positive symptoms of schizophrenia.
All antipsychotic drugs capable of treating positive psychotic symptoms are blockers of the dopamine D2 receptor. These observations have been formulated into a theory of psychosis sometimes referred to as the “dopamine hypothesis of schizophrenia” or “mesolimbic dopamine hypothesis of positive symptoms of schizophrenia.”
Hyperactivity of the mesolimbic dopamine pathway hypothetically accounts for positive psychotic symptoms whether those symptoms are part of the illness of schizophrenia, or of drug-induced psychosis, or whether they are positive psychotic symptoms accompanying mania, depression, or dementia.
Hyperactivity of mesolimbic dopamine neurons may also play a role in aggressive and hostile symptoms in schizophrenia and related illnesses.
Hyperactivity of the mesolimbic dopamine pathway hypothetically accounts for
positive psychotic symptoms whether those symptoms are part of the illness of schizophrenia, or of drug-induced psychosis, or whether they are positive psychotic symptoms accompanying mania, depression, or dementia.
Hyperactivity of mesolimbic dopamine neurons may also
play a role in aggressive and hostile symptoms in schizophrenia and related illnesses.
Mesocortical dopamine pathway and cognitive, negative, and affective symptoms of schizophrenia arises from
cell bodies in the ventral tegmental area, but projecting to areas of the prefrontal cortex, is known as the mesocortical dopamine pathway.
Branches of this pathway into the dorsolateral prefrontal cortex are hypothesized to regulate cognition and executive functions.
Branches of this pathway into the ventromedial parts of the prefrontal cortex are hypothesized to regulate emotions and affect.
Many researchers believe that cognitive and some negative symptoms of schizophrenia may be due to a deficit of dopamine activity in mesocortical projections to the dorsolateral prefrontal cortex, whereas affective and other negative symptoms of schizophrenia may be due to a deficit of dopamine activity in mesocortical projections to the ventromedial prefrontal cortex.
Many researchers believe that cognitive and some negative symptoms of schizophrenia may be due to
A deficit of dopamine activity in the mesocortical projections to the dorsolateral prefrontal cortex, whereas affective and other negative symptoms of schizophrenia may be due to a deficit of dopamine activity in the mesocortical projections to the ventromedial prefrontal cortex.
The mesocortical dopamine pathway and cognitive, negative, and affective symptoms of schizophrenia arise from
cell bodies in the ventral tegmental area, but projecting to areas of the prefrontal cortex, is known as the mesocortical dopamine pathway.
Branches of this pathway into the dorsolateral prefrontal cortex are hypothesized to regulate cognition and executive functions.
Branches of this pathway into the ventromedial parts of the prefrontal cortex are hypothesized to regulate emotions and affect.
Many researchers believe that cognitive and some negative symptoms of schizophrenia may be due to a deficit of dopamine activity in mesocortical projections to the dorsolateral prefrontal cortex, whereas affective and other negative symptoms of schizophrenia may be due to a deficit of dopamine activity in mesocortical projections to the ventromedial prefrontal cortex.
Mesocortical dopamine pathways branching into the dorsolateral prefrontal cortex are hypothesized to
regulate cognition and executive functions.
Mesocortical dopamine pathways branching into the ventromedial parts of the prefrontal cortex are hypothesized to
to regulate emotions and affect.
Therapeutic Dilemma…
Theoretically, increasing dopamine in the mesocortical dopamine pathway might improve negative, cognitive, and affective symptoms of schizophrenia. However, since there is hypothetically an excess of dopamine elsewhere in the brain – within the mesolimbic dopamine pathway – any further increase of dopamine in that pathway would actually worsen positive symptoms.
How does one increase dopamine in the mesocortical pathway while simultaneously decreasing dopamine activity in the mesolimbic dopamine pathway? Enters the Atypical Antipsychotics -
Glutamate Hypothesis and NMDA Receptor Hypofunction Hypothesis
Excess Glutamate
Decreased GABA
NMDA receptor antagonist PCP has been shown to induce the positive, negative, and cognitive symptoms of schizophrenia in healthy patients and cause a resurgence of symptoms in stable patients. These observations led to the NMDA receptor hypofunction hypothesis as an alternative theory for the underlying cause of schizophrenia.
First Generation Antipsychotics (FGAs)
FGAs are also known as typical antipsychotics, conventional or classic antipsychotics, and dopamine receptor antagonists (DRAs)
FGAs reduce dopaminergic neurotransmission in the four dopamine pathways by blocking D2 receptors.
Although individual effects may vary from patient to patient, in general, conventional antipsychotics share the same primary mechanism of action and do not differ much in their therapeutic profiles. There are, however, differences in secondary properties, such as degree of muscarinic, histaminergic, and/or alpha adrenergic receptor antagonism, which can lead to different side-effect profiles.
Largely effective for positive symptoms
Highly effective for all disorders that result in psychotic thought processes
Acute and chronic neurological side effects can limit their effectiveness
Relatively ineffective for negative symptoms
Start low and go slow
Be sure to review clinical guidelines in Kaplan & Sadock on page 622 paying attention to contraindications under the heading “Dosage & Clinical Guidelines.
FGAs differ in
potency & side effects, not necessarily effectiveness.
High-potency FGAs
haloperidol, fluphenazine
Mid-potency FGAs
perphenazine, loxapine
Low-potency FGAs
chlorpromazine
Commonly used first-generation antipsychotics -
Haloperidol (Haldol), Fluphenazine (Prolixin), Thioridazine (Mellaril), Trifluoperazine (Stelazine)
Chronic dopamine blockage can lead to
Tardive Dyskinesia (TD)
If develops EPS give
Benztropine or Trihexyphenidyl or Diphenhydramine
If develops TD give
Diphenhydramine
If develops pseudoparkinsonism reaction
try Trihexyphenidyl or Benztropine
Elevated prolactin levels ARE/ CAUSE
Blockade of the dopamine receptors in the tuberoinfundibular tract results in the increased secretion of prolactin, which can result in breast enlargement, galactorrhea, amenorrhea, and inhibited orgasm in women and impotence in men. The SDAs, with the exception of risperidone (Risperdal), are not particularly associated with an increase in prolactin levels and may be the drugs of choice for persons experiencing disturbing side effects from increased prolactin release.
Stimulation of serotonin 2A receptors stimulates prolactin release. Since they have opposing effects on prolactin, adding serotonin 2A antagonism to dopamine 2 antagonism results in a neutral effect on prolactin and may relieve breast secretions caused by dopamine 2 antagonism alone.
Neuroleptic Malignant Syndrome (NMS)
Idiosyncratic reaction to dopamine antagonists (more common in patients who are antipsychotic-naive)
Capable of producing significant mortality
Has been reported with almost all D1 & D2 antagonists including non-psychotropics such as Metoclopramide.
What Makes an Antipsychotic “Atypical”?
From a clinical perspective:
“Atypical antipsychotic” is defined in part by the “atypical” clinical properties that distinguish such drugs from conventional antipsychotics.
Atypical antipsychotics have the clinical profile of equal positive symptom antipsychotic actions, but low extrapyramidal symptoms and less hyperprolactinemia compared to conventional antipsychotics.
They also have antidepressant actions alone and in combination with other antidepressants.
They are “atypical” from what is expected from a classical, conventional, first-generation antipsychotic.
Almost all of the agents with this atypical profile came after the introduction of clozapine, sometimes the atypical antipsychotics are also called second-generation antipsychotics.
From a pharmacological perspective:
Current atypical antipsychotics as a class are defined as serotonin–dopamine antagonists, with simultaneous serotonin 5HT2A receptor antagonism that accompanies D2 antagonism.
Pharmacologic actions in addition to 5HT2A antagonism that can hypothetically also mediate the atypical antipsychotic clinical profile of low EPS and less hyperprolactinemia with comparable antipsychotic actions include partial agonist actions at 5HT1A receptors and partial agonist actions at D2 receptors.
Atypical antipsychotics as a class have the most complicated pattern of binding to neurotransmitter receptors of any drug class in psychopharmacology, and no two agents have an identical portfolio.
MOA of SGAs vs. FGAs
The presumed antipsychotic effects of the SGAs are blockade of D2 dopamine receptors. Where the SGAs differ from older antipsychotic drugs is their higher ratio interactions with serotonin receptor subtypes, most notably the 5-HT2A subtype, as well as with other neurotransmitter systems.
Hypothesized that these properties account for the distinct tolerability profiles associated with each of the SGAs.
All SGAs have different chemical structures, receptor affinities, and side effect profiles. No SDA is identical in its combination of receptor affinities, and the relative contribution of each receptor interaction to the clinical effects is unknown.
SGAs Antidepressant Actions
Beyond antagonism of 5HT2A and D2 receptors, atypical antipsychotics interact with multiple other receptor subtypes for both dopamine and serotonin and have effects on other neurotransmitter systems as well. Receptor binding properties linked to various serotonin receptors including 5HT1A partial agonist actions and antagonism of 5HT1B/D, 5HT2C, 5HT3, and 5HT7 receptors. Additional mechanisms linked to antidepressant actions that are shared by various atypical antipsychotics include:
Serotonin and/or norepinephrine reuptake inhibition – Only quetiapine (Seroquel) has potency greater than its D2 binding, ziprasidone (Geodon) has weak binding at these sites.
Alpha-2 (α2) antagonism – The proven antidepressant mirtazapine is best known for α2 antagonism, but several atypical antipsychotics also have this action with variable degrees of potency, including essentially all the “pines” (higher potency especially for quetia pine [Seroquel] and cloza pine [Clozaril]) and “dones” (higher potency especially for risperi done [Risperidal]) as well as aripiprazole (Abilify).
SGAs Antimanic Actions
All antipsychotics are effective for psychotic mania, but atypical antipsychotics appear to have greater efficacy for nonpsychotic mania, leading to the major hypothesis - D2 antagonism/partial agonism combined with 5HT2A antagonism.
SGAs Antianxiety Actions
Use of atypical antipsychotics for the treatment of various anxiety disorders is controversial. There are some studies which suggest efficacy of various atypical antipsychotics for generalized anxiety disorder, and to augment other agents for other anxiety disorders. Most controversial is their use in PTSD. The one caveat to this is the anecdotal use as well as clinical evidence for utility in various anxiety disorders is greatest for quetiapine (Seroquel).
SGAs Sedating Actions
The good - With short-term treatment, sedation is a desired therapeutic effect, especially early in treatment, during hospitalization, and when patients are aggressive, agitated, or needing sleep induction.
The bad - With long-term treatment, sedation is generally a side effect to be avoided because diminished arousal, sedation, and somnolence can lead to cognitive impairment. When cognition is impaired, functional outcomes are compromised.
Generally speaking, the pines are more sedating than the dones
SGAs Potent antihistamine actions
Clozapine, quetiapine, olanzapine, and iloperidone. All other antipsychotics have moderate potency, except lurasidone, which has essentially no binding to H1
SGAs Cardiometabolic Actions
All atypical antipsychotics share a class warning for causing weight gain and risks for obesity, dyslipidemia, diabetes, accelerated cardiovascular disease, and even premature death.
SGAs High metabolic risk –
clozapine, olanzapine
SGAs Moderate metabolic risk –
risperidone, paliperidone, quetiapine, iloperidone (weight only)
SGAs Low metabolic risk –
ziprasidone, aripiprazole, lurasidone, iloperidone (low for dyslipidemia), asenapine
Clinical Pearls -
Olanzapine is one of the antipsychotics most associated with weight gain and metabolic risk and would not be a first-line option for patients who have a primary concern about metabolic issues.
Quetiapine can lead to weight gain and increased triglyceride levels and may be a second-line option if a primary concern is metabolic issues.
Risperidone can lead to weight gain and increased triglyceride levels and may be a second-line option if a primary concern is metabolic issues.
Ziprasidone in general seems to be weight neutral and has been shown to lower triglyceride levels. It is therefore a recommended choice for individuals for whom metabolic issues are a primary concern.
Olanzapine is one of the antipsychotics most associated with
weight gain and metabolic risk and would not be a first-line option for patients who have a primary concern about metabolic issues.
Quetiapine can lead to
weight gain and increased triglyceride levels and may be a second-line option if a primary concern is metabolic issues.
Risperidone can lead to
weight gain and increased triglyceride levels and may be a second-line option if a primary concern is metabolic issues. As well as glycomastica
Ziprasidone in general seems to be weight neutral and has been shown to lower triglyceride levels. It is therefore a recommended choice for individuals for whom metabolic issues are a primary concern.
Risperidone can lead to
weight gain and increased triglyceride levels and may be a second-line option if a primary concern is metabolic issues. As well as glycomastica
Ziprasidone in general seems to be weight neutral and has been shown to lower triglyceride levels. It is therefore a recommended choice for individuals for whom metabolic issues are a primary concern.
Risperidone can lead to
weight gain and increased triglyceride levels and may be a second-line option if a primary concern is metabolic issues. As well as glycomastica
Ziprasidone in general seems to be
weight neutral and has been shown to lower triglyceride levels. It is therefore a recommended choice for individuals for whom metabolic issues are a primary concern.
Atypical antipsychotics have the clinical profile of
equal positive symptom antipsychotic actions, but low extrapyramidal symptoms and less hyperprolactinemia compared to conventional antipsychotics.
From a pharmacological perspective, current atypical antipsychotics as a class are defined as
serotonin–dopamine antagonists, with simultaneous serotonin 5HT2A receptor antagonism that accompanies D2 antagonism
actions include partial agonist actions at 5HT1Areceptors
Atypical antipsychotics antidepressant action - Serotonin &/or norepinephrine reuptake inhibitor
Only quetiapine (Seroquel) has potency greater than its D2 binding,
ziprasidone (Geodon) has weak binding at these sites.
Atypical antipsychotics antidepressant action - Alpha-2 antagonism
The proven antidepressant mirtazapine is best known for α2 antagonism
Several atypical antipsychotics also have this action with variable degrees of potency, including
Essentially all the “pines” (higher potency especially for quetia pine [Seroquel] and clozapine [Clozaril])
And “dones” (higher potency especially for risperi done [Risperidal]) as well as aripiprazole (Abilify).
Atypical Antipsychotics sedating actions
Generally speaking, the pines are more sedating than the ones
The good - With short-term treatment, sedation is a desired therapeutic effect, especially early in treatment, during hospitalization, and when patients are aggressive, agitated, or need sleep induction.
The bad - With long-term treatment, sedation is generally a side effect to be avoided because diminished arousal, sedation, and somnolence can lead to cognitive impairment. When cognition is impaired, functional outcomes are compromised.
atypical antipsychotics potent antihistamine actions –
Clozapine, quetiapine, olanzapine, and iloperidone.
All other antipsychotics have moderate potency, except lurasidone, which has essentially no binding to H1
Psychosis- a conditions that
affect the mind, where there has been some
loss of contact with reality. When someone becomes ill in this way it is
called a psychotic episode. During a period
of psychosis, a person’s thoughts and
perceptions are disturbed and the
the individual may have difficulty understanding
what is real and what is not
Illusion-
misrepresentation of a “real” sensory stimulus
Hallucinations-
defined as the perception of an object or event (in any of the 5 senses) in the absence of an external stimulus, are experienced by patients with conditions that span several
fields.
Delusions-
are false beliefs based on incorrect inferences about an external reality that persists despite the evidence to the contrary;
these beliefs are not ordinarily accepted by other members of the person’s culture or subculture.
Schizophrenia - DSM 5
A. Two or more of the following for at least a one-month (or longer) period of time, and at least one of them must be 1, 2, or 3:
1. Delusions
2. Hallucinations
3. Disorganized speech
4. Grossly disorganized or catatonic behavior
5. Negative symptoms, such as diminished emotional expression
C. Duration: Continuous signs of the disturbance persist for at least 6 months. This 6-month period must include at least one month of symptoms (or less if successfully treated) that meet Criterion A (i.e., active-phase symptoms) and may include periods of prodromal or residual symptoms. During these prodromal or residual periods, the signs of the disturbance may be manifested by only negative symptoms or two or more symptoms listed in Criterion A present in an attenuated form (e.g., odd beliefs, unusual perceptual experiences).
D. Schizoaffective disorder and depressive or bipolar disorder with psychotic features have been ruled out because either (1) no major depressive or manic episodes have occurred concurrently with the active-phase symptoms, or (2) if mood episodes have occurred during active-phase symptoms, they have been present for a minority of the total duration of the active and residual periods of the illness.
E. The disturbance is not attributable to the physiological effects of a substance (e.g., a drug of abuse, a medication) or another medical condition.
F. If there is a history of autism spectrum disorder or a communication disorder of childhood onset, the additional diagnosis of schizophrenia is made only if prominent delusions or hallucinations, in addition to the other required symptoms of schizophrenia, are also present for at least 1 month (or less if successfully treated).
Schizoaffective DSM 5
A. Schizoaffective disorder debut has an uninterrupted period of illness, during which
there is an episode of mood disorder (manic or major depressive disorder) concurrent with a schizophrenia episode characterized by 2 or more of the following symptoms present for a considerable part of a 1-month period:
* delusions
* hallucinations
* disorganized speech (e.g., frequent derailment or incoherence)
* grossly disorganized or catatonic behavior
* negative symptoms (i.e. affective
flattening, alogia, or avolition).
B. During this time, there should be a period of at least 2 weeks with delusions and
hallucinations, in the absence of prominent mood symptoms during the lifetime duration of illness.
C. Mood symptoms have been present for the majority of the total duration of the
active and residual period of illness
Delusional Disorder
The presence of one or more delusions for a month or longer in a person who, except for the delusions and their behavioral ramifications doesn’t appear odd and is not functionally impaired
can be either
with non-bizarre delusions are about situations that could occur in real life, such as being followed, being loved, having an infection, and being deceived by one’s spouse
or
with bizarre delusions that are clearly implauable
Unspecified Schizophrenia Spectrum Disorder
The category of unspecified psychotic disorder includes psychotic symptomatology (i.e., delusions, hallucinations, disorganized speech, grossly disorganized or catatonic behavior) about which there is inadequate
information to make a specific diagnosis or about which there is contradictory information, or disorders with psychotic symptoms that do not meet the
criteria for any specific psychotic disorder.
ETIOLOGY
Genetic factors
The likelihood is correlated with first-degree or second-degree relative with schizophrenia; 50% concordance with monozygotic twins
Biochemical Factors
Dopamine hypothesis of too much dopamine-unsure if too much release, too many dopamine receptors, hypersensitivity to dopamine receptors, or combinations
Serotonin-too much?
GABA-inhibitory affect preventing from regulation of dopamine and causing hyperactivity of dopaminergic neurons
Neuropathology
Reduced volumes of gray matter and enlarged cerebral ventricles
Reduced symmetry and reduced limbic system
Anatomical abnormality of the pre-frontal cortex
FGA/TYPICAL ANTIPSYCHOTICS
FGAs are also known as typical antipsychotics, conventional or classic antipsychotics, and dopamine receptor
antagonists (DRAs) *
FGAs reduce dopaminergic neurotransmission in the four dopamine pathways by blocking D2 receptors.
Although individual effects may vary from patient to patient, in general, conventional antipsychotics share the same primary mechanism of action and do not differ much in their therapeutic profiles.
There are, however, differences in secondary properties, such as degree of muscarinic, histaminergic, and/or alpha adrenergic receptor antagonism, which can lead to different side-effect profiles.
Largely effective for positive symptoms
Highly effective for all disorders that result in psychotic thought processes
Relatively ineffective for negative symptoms
Specific FGAs to know
Chlorpromazine (Thorazine)
Prochlorperazine (Compazine)
Perphenazine (Trilafon)
Trifluoperazine (Stelazine)
Fluphenazine (Prolixin)
Haloperidol (Haldol)
Loxapine (Loxitane)
Thioridiazine (Mellaril)
INDICATIONS FOR TYPICALS
Acute psychotic episodes, schizophrenia,
and schizoaffective
Maintenance of schizophrenia and
schizoaffective disorders
Mania
Delirium and dementia
Substance-induced psychotic disorder
Delusional disorder
Depression with psychotic symptoms
Undesirable Effects: STANCE
S: sedation/sunlight sensitivity skin effects/sexual side effects
T: tardive dyskinesia
A: anticholinergic effects & agranulocytosis
N: neuroleptic malignant syndrome
C: cardiac arrhythmias (orthostatic hypotension)
E: extrapyramidal symptoms /akathisia endocrine effects - increased prolactin eye effects
EXTRAPYRAMIDAL SYMPTOMS (EPS)
Akathisia, Acute Dystonic Reactions, Parkinsonism
Chronic dopamine blockage can lead to Tardive Dyskinesia (TD)
If develops EPS give Benztropine or Trihexyphenidyl or Diphenhydramine
Propranolol more beneficial for akathisia
If develops TD give Diphenhydramine, weak studies Vitamin E use, change to a different antipsychotic with less potential
Pseudoparkinsonism
Stooped posture
Shuffling gate
Rigidity
Bradykinesia
Tremors at rest
Pill-rolling motion of the hands
Acute dystonia
Facial Grimacing
Involuntary upward eye movement
Muscle spasms of the tongue, face, neck, and back (back muscle spasms cause the trunk to arch forward
Laryngeal spasms
Akathisia
Restlessness
trouble standing still
paces the floor
feet in constant motion, rocking back and forth
Tardive dyskinesia
Protrusion and rolling of the tongue
sucking and smacking movements of the lips
chewing motion
facial dyskinesia
involuntary movements of the body and extremities
EXTRAPYRAMIDAL SYMPTOMS TREATMENT Acute Dystonic Reaction
Duration to implement tx - Minutes-hours
Tx options - Benztropine or other anticholinergic PO or IM
EXTRAPYRAMIDAL SYMPTOMS TREATMENT Psuedoparkinsonism
Duration to implement tx - Days
Tx options - Benzodiazepine
EXTRAPYRAMIDAL SYMPTOMS TREATMENT Akathesia
Duration to implement tx - Days - Weeks
Tx options - Benzodiazepine, beta-blockers
EXTRAPYRAMIDAL SYMPTOMS TREATMENT Tardive Dyskinesia
Duration to implement tx - Long term
Tx options - Switch to atypical or clozapine, Vesicular Monoamine transporter 2 inhibitor
Dystonia
More common with high potency typical antipsychotics (rare with atypical antipsychotics); D2 blockade
Onset in hours to days after antipsychotic started or dose increased; 90% within first 5 days
Benztropine 1-2mg 1-twice /day (SE: dry
mouth, blurred vision, constipation, urinary retention, cognitive changes) Diphenhydramine 50mg/day
If severe, stop the medication and give
above agents IV or IV once or twice
to stop the dystonia; then prescribe
oral medication to prevent another
episode
PARKINSONISM
Pseudo parkinsonism—drug induced Parkinson’s like disease (Tremor “pill rolling”, rigidity or cogwheeling, bradykinesia-(slow movement), shuffling gait; slurred speech, mask like face, stooped posture, drooling;
cognitive dulling, worse negative symptoms, worse depression.
*Decrease the dose or switch to a different
antipsychotic
*First-line meds: Benztropine 1-2mg once or twice per day;
*trihexyphenidyl 2-5mg once or twice per day; diphenhydramine 50mg /day
*Symptoms can occur at any time; usually occurs within 1-2 months after antipsychotic initiated; highest risk patients: female, older higher potency agents at higher doses
*If the patient is at high risk for parkinsonism—start benztropine (or one of the first-line agents) at
the same time as starting the antipsychotic
*Can discontinue the anticholinergic agent after several weeks; many patients will not need to remain on it long term
*Usually caused by typical agents. Atypical can cause this also. (Meds least likely to cause this: clozapine, quetiapine, and
ziprasidone.) *D2 blockade—disruption
of balance b/t dopaminergic vs cholinergic neurons
Akathisia
Sense of restlessness, appear fidgety, can’t sit still, rocking motion; can be inner sense of restlessness; can lead to agitation and suicidal ideation; appears in days to weeks after starting medication
High potency typical agents most likely to cause this (Haloperidol); atypical aripiprazole, asenapine, brexpiprazole, cariprazine, lurasidone, paliperidone, risperidone;
SSRIs/Buspirone); D2 blockade
First-line medications to treat:
*Propranolol-Start 10mg BID; can go up to 30mg-90mg daily in 2-3 divided doses (SE: dizziness, fatigue, syncope, low BP)
*Inderal LA—long-acting propranolol dosed once a day (60- 80mg daily)
*Benzodiazepines-any of them will work. (Eg Lorazepam 0.5mg to 1mg BID) or diazepam 10mg BID or more frequently as needed
Reduce dose of medication; switch to lower potency agent or different atypical agent
*Don’t mistaken akathisia with agitation for psych disorder symptoms; you may worsen akathisia. (Clozapine, quetiapine, and lurasidone cause no more akathisia than placebo)
TREATMENT FOR TARDIVE DYSKINESIA
First line med
Deutetrabenazine (Austedo)
DOSE
6mg BID for 1 week, then raise based on response by 3mg BID every week max
24mg BID; take with food
RISK
QTc prolongation,
insomnia, nasopharyngitis, possible depression, and suicidality
NOTES
These usually need to
ordered through a specialty
pharmacy ($6000/mth)
First line med
Valbenazine (Ingrezza)
DOSE
40mg QHS for 1 week,
then 80mg QHS with or
without food
RISK
QTc prolongation, sedation,
possible depression and
suicidality
TARDIVE DYSKINESIA (TD) TREATMENT MANAGEMENT
Step 1
Prevention-minimizing antipsychotics in patients at risk. Risk factors: Age>50; h/o SUD, brain injury, diabetes, HIV+, female gender, mood disorders, African American race, and presence of EPS
* Minimize the dose and duration if taking an antipsychotic
* Can decrease duration in mood disorders/not likely in schizophrenia
Step 2
Taper off with first signs of TD; discuss risks/benefits to continued treatment with antipsychotic
* d/c dose-lower the dose every 2-4 weeks
* Can have ‘withdrawal dyskinesias’ with worsening dyskinesias for the first few months after med is stopped
* Can be permanent, 30-50% of cases can resolve with discontinuation.
Step 3
Switch- if discontinuation is not successful.
* Clozapine is the only antipsychotic that does not cause TD (Low level of D2 occupancy) (has other risks) (Quetiapine also has a low level of D2 occupancy & low EPS rates)
* Aripiprazole, and olanzapine may be good alternatives
Step 4
VMAT2 inhibitor—if tapering and switching do not work-attempt to treat TD
* Valbenazine (Ingrezza)—take 1 time a day (1 in 4 response rates) & deutetrabenazine
(Austedo) Take BID with food (1 in 7 response rates) (H/o causing depress/suicide in past—has black box warning for Huntington’s for suicidality )
* Reduces dopamine hypersensitivity ; Don’t worsen psychosis; actually have been helpful in past for treating psychosis (reserpine)
* Take 4-6 weeks to work; continue as long as patient is taking the antipsychotic; or TD will
return within a mth of d/c
Step 5
Second line agents- dopamine agents that address other pathways such as glutamate antagonist- amantadine-tx’s dyskinesias in Parkinson’s disease; Ginkgo is neuroprotective; benztropine can
worsen TD with his anticholinergic effects
NEUROLEPTIC MALIGNANT SYNDROME
NMS is a life-threatening emergency and is fatal in 10% of cases. It usually occurs later in
treatment but can occur earlier.
It is characterized by:
Reduced consciousness
Increased muscle tone
Autonomic dysfunction (hyperpyrexia, hypertension, tachycardia, tachypnea, diaphoresis, and drooling)
*Treatment consists of early detection, discontinuation of antipsychotics, management of fluid balance, temp. reduction, and monitoring for complications.
DRUG INTERACTIONS
Anticholinergics-decreases antipsychotic effect
Barbiturates-decreases antipsychotic concentrations
Carbamazepine-up to 50% reduction in antipsychotic concentrations
Cigarette smoking-Reduced plasma concentration of antipsychotic agents
Fluvoxamine-increases haloperidol and clozapine concentrations
Amphetamines-may exacerbate psychosis
Benzodiazepines-Respiratory depression, stupor, and hypotension
Clonidine-hypotension or hypertension-potentiate alpha effects
Valproate Acid-Increases half-life and levels
USUAL DOSAGES - Haloperidol (Haldol)
Range
1- 40mg daily Decanoate: 10-20 times
the previous oral dose/2 weeks
How to dose-
Oral: 1-15mg/day can give once daily
or divided doses; not more than
100mg/day
USUAL DOSAGES - Fluphenazine (Prolixin)
Range
1-20mg/day Decanoate: 12.5-100mg/2
weeks
How to dose
Oral: 0.5-10mg/day in divided doses:
max: 40mg/day
USUAL DOSAGES - Chlorpromazine (Thorazine)
Range
200-800mg/day
How to dose -
Initial: dose increased until symptoms controlled
USUAL DOSAGES - Loxapine (Loxitane)
Range
60-100 mg/day in divided doses
How to dose -
Initial 20mg/day in 2 doses titrate
over 7-10 days to 60-100mg/day in 2-
4 doses; max: 250mg/day
USUAL DOSAGES - Perphenazine (Trilafon)
Range
12-24mg/day; 16-64mg hospital pts.
How to dose -
Initial: 4-8 mg TID; 8-16mg BID-QID
hospital pts.; Max: 64mg/day
USUAL DOSAGES - Trifluoperazine (Stelazine)
Range
15-20mg/ day
How to dose -
Initial: 2-5 mg/day BID
SGA/ ATYPICAL ANTIPSYCHOTICS - From a clinical perspective
From a clinical perspective:
* “Atypical antipsychotic” is defined in part by the “atypical” clinical properties that distinguish such drugs from conventional antipsychotics.
- Atypical antipsychotics
- Have the clinical profile of equal positive symptom antipsychotic actions, but low extrapyramidal symptoms and less hyperprolactinemia compared to conventional antipsychotics.
- They also have antidepressant actions alone and in combination with other antidepressants.
- Beyond antagonism of 5HT2A and D2 receptors, atypical antipsychotics interact with multiple other receptor subtypes for both dopamine and serotonin and have effects on other neurotransmitter systems as well
- They are “atypical” from what is expected from a classical, conventional, first-generation antipsychotic.
MECHANISM OF ACTION: SGA VS FGA
The presumed antipsychotic effects of the SGAs are blockade of D2 dopamine receptors.
Where the SGAs differ from older antipsychotic drugs is their higher ratio interactions with serotonin receptor subtypes, most notably the 5-HT2A subtype, as well as with other neurotransmitter systems.
Hypothesized that these properties account for the distinct tolerability profiles associated with each of the SGAs.
All SGAs have different chemical structures, receptor affinities, and side effect profiles.
Beneficial for both negative and positive symptoms.
SGA/ATYPICAL ANTIPSYCHOTICS to know
Clozapine (Clozaril)
Risperidone (Risperdal)
Olanzapine (Zyprexa)
Quetiapine (Seroquel)
Ziprasidone (Geodon)
Aripiprazole (Abilify)
Paliperidone (Invega)
Asenapine (Saphris)
Iloperidone (Fanapt)
Lurasidone (Latuda)
Brexpiprazole (Rexulti)
Cariprazine (Vraylar)
INDICATIONS FOR ATYPICALS
Schizophrenia
Behavioral disturbances with dementia
Treatment-resistant depression
Autism Spectrum Disorders
Post Traumatic Stress Disorder
Anxiety disorders
Adjunctive treatment of depression
Acute Mania
SGA ADVERSE EFFECTS
*Many of the same side effects of
FGAs-
one disadvantage of atypicals
is the tendency to gain weight and
put patients at risk for Metabolic
Syndrome which consists of :
(Weight gain, Dyslipidemia, Altered
glucose metabolism, & Hypertension)
High Metabolic Risk-
Clozapine, Olanzapine
Moderate metabolic Risk-
risperidone, paliperidone, quetiapine,
iloperidone (weight only)
Low metabolic risk-
ziprasidone, aripiprazole, lurasidone,
iloperidone (low for dyslipidemia), asenapine
SGA Clinical Pearls
- Olanzapine is one of the antipsychotics most associated with weight gain and
metabolic risk - Quetiapine can lead to weight gain and increased triglyceride levels and may be a second-line options if a primary concern is metabolic issues
- Risperidone can lead to weight gain and increased triglyceride levels and may be a second-line options if a primary concern is metabolic issues.
- Ziprasidone in general seems to be weight neutral and has been shown to
lower triglyceride levels.
Elevated prolactin levels
- Blockade of the dopamine receptors in the tuberoinfundibular tract results in the increased secretion of prolactin, which can result in breast enlargement, galactorrhea, amenorrhea, and inhibited orgasm in women and impotence in men.
- The SGAs, apart from risperidone (Risperdal), are not particularly associated with an increase in prolactin levels and may be the drugs of choice for persons experiencing disturbing side effects from increased prolactin release.
- Stimulation of the serotonin 2A receptors stimulates prolactin release
SGA SIDE EFFECTS - weight gain
- Clozapine is the worst, then olanzapine, quetiapine, and risperidone, paliperidone (in descending order)
- Other SGAs are close to a weight neutral in adults. Kids still tend to gain weight despite neutral meds
- Weight gain and metabolic effects are the greatest in the pediatric population
- All labels with FDA warning for weight gain, hyperglycemia, new-onset or worsening diabetes and
hyperlipidemia
SGA SIDE EFFECTS - Sedation
- Clozapine, olanzapine, quetiapine are most sedating. ‘Revved up psychosis” will do well on these.
- May need an alternative antipsychotic for long-term treatment if too sedating
SGA SIDE EFFECTS - cardiac issues
EKG changes-ziprasidone is most prevalent with increased QT interval and can cause serious arrhythmias
* Actual risk is only 0.06%.
Others that cause QT prolongation: are thioridazine (Mellaril), iloperidone (Fanapt),
quetiapine (Seroquel)
SIDE EFFECTS - EPS
- EPS among the FGAs—Haloperidol and fluphenazine (Prolixin) cause the most EPS
- Among the SGAs: risperidone is the highest EPS risk
- Highest risk with SGAs to cause akathisia:
aripiprazole (Abilify) & brexpiprazole (Rexulti)
USUAL DOSE (Range & How to dose) - Clozapine (Clozaril)
Depends on plasma levels; trough level of
350 ng/mL
25mg qhs; increase by 25-50mg every 48-72
hours as tolerated
USUAL DOSE (Range & How to dose) - Aripiprazole ( Abilify)
15-30mg/day schizo and mania 2-10mg/day
augment depression Decanoate: 300-
400mg/ 4 weeks
Oral: 10-15mg/day initial; max: 30mg/day-
schizo/mania 2-5mg/day
USUAL DOSE (Range & How to dose) - Risperidone (Risperdal)
2-8mg/day psychosis or bipolar
0.5-2mg/day for children and elderly
12.5mg-50mg IM every 2 weeks
1mg/day orally in BID; increase 1mg each day as tolerated
USUAL DOSE (Range & How to dose) - Quetiapine (Seroquel)
400-800mg/day- Schizo
300mg/day Bipolar Depression
25mg BID and increase by 25-50mg twice a
day each day; max: 800mg
Acute mania: 100mg day 1 and increase to 400mg/day on day 4
USUAL DOSE (Range & How to dose) - Olanzapine (Zyprexa)
10-20mg/day
5-10mg/day increase by 5mg once a week until desired efficacy
USUAL DOSE (Range & How to dose) - Ziprasidone (Geodon)
40mg-200mg/day schizo;
80- 160mg/day Bipolar
Schizo: initiate 20mg BID with food/
Bipolar: initiate 40mg BID
USUAL DOSE (Range & How to dose) - Paliperidone (Invega)
6mg/day Sustenna: 39-234mg/month
6mg/day taken in the morning; increase by 3mg/day
every 5 days
USUAL DOSE (Range & How to dose) - Asenapine (Saphris)
10-20mg/day BID dose- Sublingual
Children: 5mg BID; max 10mg/day
10mg/day- do not eat or drink for 10 mins.
after
USUAL DOSE (Range & How to dose) - Iloperidone (Fanapt)
12-24mg/day in BID dosing
2mg/day 1; 4mg/day 2; 8mg/day 3,
12mg/day on day 4; 16mg day 5
USUAL DOSE (Range & How to dose) - Lurasidone (Latuda)
40mg-80mg/day Schizophrenia
20-60mg/day Bipolar
Take with food; 40-80mg/day increase as
tolerated
USUAL DOSE (Range & How to dose) - Brexpiprazole (Rexulti)
2-4mg/day Schizo
2mg/day Depression
1mg/day on days 1-4;
2mg on day 5- 7, and
4mg day 8 if needed
USUAL DOSE (Range & How to dose) - Cariprazine (Vraylar)
1.5-6mg once daily Schizo 3-6mg/day
daily
1.5mg/day on day 1 and can increase to 3mg
day 2
CLINICAL TREATMENT TIDBITS
Contraindications of treatment- allergic response history, ingestion of substance that may interact with antipsychotic, severe cardiac abnormality, high risk for seizures, narrow angle glaucoma, and presence of TD.
Usual assessment of CBC, LFTs, and EKG
Elderly and children more sensitive to treatment
Start low and go slow
Maximal effects of particular dose may not be evident for 4-6 weeks
First 3-6 mos. After a psychotic episode are usually considered period of stabilization- dosage can be decreased about 20% every 6 mos. Until minimum effective dose is found.
Persons usually maintained on antipsychotic 1 to 2 years after first psychotic episode; usually 5 years after 2nd episode;
lifetime maintenance after 3rd psychotic episode
LONG-ACTING DEPOT MEDICATIONS
May overcome problems with compliance
IM preparations usually give every 1- 4 weeks
May have to adjunct with oral medications initially until dose is therapeutic
After 3 to 4 weeks injection dose can be increased to single dose equal to total dose of drug given during period
