Stoletin 45 - Neuroleptic Complications and Management

• Psychopharmacologic therapeutics target various aspects of central nervous system neuronal function.
• These include drugs developed primarily for psychiatric indications and those borrowed from other medical fields like neurology and anesthesiology.
• Classification systems based on indication (anxiolytics, antidepressants, antipsychotics) or chemistry (benzodiazepines, tricyclics, phenothiazines) have become untenable.
• The development of safe and effective psychotherapeutic drugs allows most individuals with psychiatric disorders to be treated in ambulatory settings
• Adults with depressive mood disorders or anxiety are commonly prescribed medication by PCPs, but severe/persistent cases are handled by psychiatrists.
• According to the National Center for Health Statistics in 2017, 12.7% of Americans over 12 used antidepressant medications in the past month.
• Higher rates of antidepressant use were seen in women, non-Hispanic white Americans, and the elderly in 2017.
• Nearly 24 million antipsychotic prescriptions were issued in the US in 2017 for the top 6 most commonly prescribed drugs.
• Anesthesia is widely accepted as safe for patients on medications for mental illness.
• Drug interactions between psychopharmacologic drugs and anesthetic drugs are less significant than previously thought and discontinuing antidepressant therapy isn't justified.
• Vigilance for potential drug interactions remains important.
• Many psychotropic and anesthetic drugs interact with serotonin receptors and are metabolized by common liver enzymes, this is particularly important for the elderly.
• Anesthesiologists need to understand the pharmacology and potential side effects of the medications the patient is maintained on.

Drugs With Primarily Serotonergic Activity

• Most drugs classified as antidepressants impact serotonergic and/or noradrenergic neurotransmission.
• The effectiveness of antidepressants for depressive, anxiety, and chronic pain disorders makes the term "antidepressant" a misnomer.
• The broad effectiveness doesn't suggest a common pathophysiology but reflects the roles of monoamine neurotransmitters in the human nervous system.

Mechanisms of Action

• Serotonergic drug mechanisms are unknown, but directly increase serotonin in synapses or alter serotonin receptor signaling.
• Clinical improvement with serotonergic drugs isn't explained by acute synaptic serotonin increases, with improvement typically occurring in 2-4 weeks.
• Symptomatic improvement reflects adaptive changes from chronic exposure, such as desensitization of serotonin 5-HT1A inhibitory autoreceptors and changes in plasticity.

Serotonin Receptors

• Serotonin signaling is mediated by a large family of receptors organized into seven families
• Six of which signal via G proteins and one (5-HT3) is a ligand-gated cation channel.
• Serotonin receptors are throughout the body and regulate processes outside the CNS like motility, arousal, vascular tone, hematopoiesis, platelet aggregation, and inflammatory response.
• In the CNS, serotonergic projections from raphe nuclei targets the cortex, subcortex, cerebellum, and spinal cord, regulating neurotransmitter and hormone release.
• Serotonin influences social, affective, and cognitive functions like mood, sleep, aggression, appetite, sex, and memory.
• The inhibitory receptor 5-HT1A is key for antidepressant responses, regulating neuronal activity and target tissues.
• The excitatory 5-HT2A receptor is antagonized by atypical antipsychotics and agonized by hallucinogens, regulating cognition, attention, working memory, and psychosis.
• The 5-HT3 receptor regulates nausea and vomiting and is targeted by certain psychotropic medications.

Serotonin Reuptake Inhibitors

• Serotonin reuptake inhibitors (SRIs) are medications that bind and inhibits SERT, stopping serotonin reuptake from the synaptic cleft and enhancing neurotransmission.
• SRIs are widely used medications for treatment of psychiatric conditions.
• Common side effects of SRIs include insomnia, agitation, headache, nausea, and diarrhea, which are transient, they arise when initially introduced or dosages are increased.
• Drug-induced sexual dysfunction is an exception to the transient side effects, it is a common cause of noncompliance with SRI therapy.

Treatment-Emergent Suicidality

• In September 2004, the FDA recommended a "black box" warning for new antidepressants in SSRIs.
• This was based on evidence of increased suicidal thoughts and behaviors in children and adolescents taking SRIs compared to placebo, it did not include completed suicides.
• The warning has been criticized due to decreased rates of diagnosis and treatment for depressed children and adolescents, and no data suggested increase in suicidal behavior in adults.

Serotonin Reuptake Inhibitor Discontinuation Syndrome

• Abrupt discontinuation of SRI medications can lead to withdrawal symptoms, the SRI discontinuation syndrome has received attention as a clinical concern.
• Withdrawal symptoms are linked to SRIs with short elimination half-lives like paroxetine, venlafaxine, and duloxetine.
• These usually emerge after medication is fully discontinued, they also have higher vulnerability in patients with longer SRI use.
• The SRI discontinuation syndrome may include dizziness, flu-like myalgias, irritability, insomnia, and visual disturbances.
• Paresthesia, referred to as "brain zaps", is a common symptom, described as electrical shock-like sensations in the head.
• SRI withdrawal doesn't respond to benzodiazepines but remit with SRI reintroduction.
• Although considered medically dangerous, the withdrawal symptoms can be difficult to differentiate from interpretations of clinical condition.
• Outpatient SRI medications should be continued when possible in acute care settings given the risk of misinterpreting symptoms.
• It is recommended to use a gradual taper when discontinuing SRI medications.

Bleeding Risk

• SRI-linked risks have long been a theoretical concern, given serotonin's role in platelet aggregation.
• SRI use in older adults has been linked to increased relative, but low absolute risk of upper gastrointestinal bleeding and intracerebral brain hemorrhage.
• A recent study found no significant increase in major bleeding events for anticoagulated outpatients on SSRIs..
• A recent systematic review suggests increased bleeding risks are real in surgical settings, balancing risks against medication discontinuation risks or symptom relapse.

Hyponatremia

• Clinically significant hyponatremia is a potential complication of SRI medication.
• It’s been reported in patients with psychopharmacologic drugs, most attention given to association among drugs to treat depression and new onset hyponatremia.
• A 2004 study with paroxetine showed 12% developed hyponatremia, serum sodium below 135 mEq/L, it took approximately 9 days to initiate.
• The syndrome of inappropriate secretion of antidiuretic hormone is suggested to be the cause of hyponatremia after paroxetine.
• Studies suggest many antidepressant medications can cause hyponatremia but risk with SRI medications is higher.
• The risk is higher in women, the elderly, and those with cardiovascular comorbidity while it also diminishes after medication initiation.
• For acute care, SRI use/duration should assessed alongside clinically significant hyponatremia, switch to a non-SRI like mirtazapine and consider for discontinuation.

Serotonin Syndrome

• Serotonin syndrome, attributed to toxic levels of synaptic and extracellular serotonin, is a rare but serious complication of SRI use.
• It includes neuromuscular excitability, autonomic nervous system excitability, and mental status changes.

Selective Serotonin Reuptake Inhibitors

• The paradigmatic class of SRI medications—the SSRIs—includes the drugs fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, and escitalopram.
• SSRIs selectively block neuronal reuptake of serotonin and are the most widely prescribed psychotropics.
• SSRIs are first-line pharmacotherapy for depressive/anxiety disorders, major depressive disorder, generalized anxiety, panic attacks, social anxiety, posttraumatic stress, and obsessive-compulsive disorder.
• Compared with tricyclic medications, SSRIs have greatly reduced anticholinergic properties, contribute minimally to postural hypotension, lack cardiac impulse delays, have no major effect on the seizure threshold, and are safer in overdose.
• SSRIs have varied side effect profiles, if a patient does not respond well to one drug, another SSRI can be tried, and the effectiveness of the SSRIs are the same.

Serotonin-Norepinephrine Reuptake Inhibitors

• Many SRI medications have additional pharmacologic activities aside from SERT blockade.
• SNRIs inhibit NET and SERT, commonly prescribed as first or second-line medications for depressive/anxiety disorders.
• SNRIs: venlafaxine, desvenlafaxine, and duloxetine as well as milnacipran and levomilnacipran.
• More noradrenergic medications suggested have superior efficacy for depression treatment.
• Any greater benefit of SNRIs is balanced against poorer tolerability suggestions and concerns about hemodynamic effects.
• Systolic/diastolic blood statistically elevates with SNRI compared to SSRI medications, observed levels are clinically insignificant.
• The elevated overdose-associated risk associated with proconvulsant and cardiac side effects is one of the considerations for increased risk relative to benefit for venlafaxine.

Utility in Chronic Pain Syndromes

• SNRI medications have superior efficacy over SSRI medications for chronic pain.
• SNRI and norepinephrine reuptake inhibitor tricyclic medications are commonly used off-label to treat various forms of said pain.
• Duloxetine/milnacipran are FDA-approved for treating chronic pain syndromes, while SNSIs versus tricyclics do not have confirmed chronic pain efficacy. These medications increase engagement of descending pain systems that suppress ascending pain transmission and regulate pain homeostatically.

Tricyclic Serotonin Reuptake Inhibitors

• The class of SRI medications includes tricyclic clomipramine, FDA approved for OCD, and imipramine to treat childhood enuresis.
• Clomipramine strongly inhibits SERT while imipramine affects both, both are SNRIs due to metabolites with anticholinergic and antihistaminergic effects.

Serotonin Multimodal Drugs

• Medications that act on serotonin to inhibit SERT blockade are "multimodal", these include vortioxetine and vilazodone, which are partial agonists at the 5-HT1A receptors while acting as SRIs.
• Adverse impact profile is the same in SSRIs, efficacy for major depression related impairment.
• Vortioxetine has a half-life of 66 hours, whereas vilazodone has a half-life of 25 hours.
• Trazodone is a multimodal serotonergic, which helps treat major depression and insomnia.

Monoamine Oxidase Inhibitors

• MAOIs inhibit serotonin, norepinephrine, and dopamine.
• They're given to patients with MAOIs because of interactions with tyramine.

Dietary Restrictions

• MAO enzyme is present in the liver and kidneys and deactivates monoamines.
• This function is important in deactivating tyramine, which causes hypertension.
• The MAOIs are A and B non selectively.
• At high doses, selegiline becomes a MAIO which makes dietary precautions necessary.

Explore the immediate recognition and management of neuroleptic-induced respiratory distress, drug-induced akathisia, and tardive dyskinesia. Identify risk factors for tardive dyskinesia. Understand mechanisms of action and characteristic symptoms of Neuroleptic Malignant Syndrome (NMS) and treatment options.