Anxiolytics, Antidepressants, and Antipsychotics PDF

Anxiolytics, Antidepressants, and Antipsychotics By Colin Greengrass, Ph.D. LEARNING OBJECTIVES Outline the nature of depression and anxiety Compare the properties of anxiolytic and sedative-hypnotic drugs Outline the mechanism of action and adverse effects of benzodiazepines Co...

Anxiolytics, Antidepressants, and Antipsychotics By Colin Greengrass, Ph.D. LEARNING OBJECTIVES Outline the nature of depression and anxiety Compare the properties of anxiolytic and sedative-hypnotic drugs Outline the mechanism of action and adverse effects of benzodiazepines Compare and describe the mechanism of action and adverse effects of neurotransmitter reuptake inhibitors TCA, SSRIs, SNRIs, NDRIs Describe the mechanism of action and adverse effects of monoamine oxidase inhibitors Define the properties of newer drugs used in the treatment of depression including ketamine analogues Describe the positive, negative and cognitive symptoms of schizophrenia and their pathogenesis Describe the mechanism of action and adverse effects of 1st generation (typical) anti-psychotic agents Describe the mechanism of action and adverse effects of 2nd generation (atypical) anti-psychotic agents Describe the mechanisms of action of drugs used to treat bipolar disorder  ANXIETY Fear is a complex physiological, behavioural, cognitive response to a threatening stimulus It is an adaptive response to real threats and is usually transient THE NORMAL FEAR RESPONSE TO THREATENING STIMULI COMPRISES SEVERAL COMPONENTS DEFENSIVE AUTONOMIC AROUSAL AND CORTICOSTEROID NEGATIVE BEHAVIOURS REFLEXES ALERTNESS SECRETION EMOTIONS  ANXIETY ANXIETY IS MEANT TO INCREASE THE LIKELIHOOD OF SURVIVAL IN DANGEROUS SITUATIONS SYMPTOMS ARE INCREASED AROUSAL HYPERVIGILANCE TACHYCARDIA PHYSICAL PREPAREDNESS – SYMPATHETIC NERVOUS SYSTEM ACTIVATION  ANXIETY Anxiety is a longer-lasting response to danger It may have a specific cause related to something that can signal danger It may be caused by events that are thought or anticipated to have adverse consequences In anxiety states, these reactions occur often independently of external events ANXIETY DISORDERS ANXIETY CURRENTLY RECOGNIZED ANXIETY DISORDERS ARE GENERALIZED ANXIETY DISORDER PANIC DISORDER POST-TRAUMATIC STRESS DISORDER SOCIAL ANXIETY DISORDER SIMPLE PHOBIAS OBSESSIVE-COMPULSIVE DISORDER Therapeutic Strategies in Anxiety Disorders GAD Acute state - Benzodiazepines Chronic state – SSRI / SNRI Phobia SSRIs Propranolol and exposure therapy CBT, biofeedback  SLOW VS RAPID ACTING ANXIOLYTIC DRUGS EFFECTS WITHIN 30 MINUTES AFTER ADMINISTRATION BENZODIAZEPINES ARE RAPID CAN BE USEFUL FOR PATIENTS WHO NEED ACUTE TREATMENT ONSET ANXIOLYTIC DRUGS CAN BE TAKEN ON AN ‘AS NEEDED’ BASIS ANTIDEPRESSANTS AND REQUIRE TREATMENT FOR THREE OR MORE WEEKS TO SHOW BUSPIRONE ARE SLOW ONSET ANY THERAPEUTIC EFFECT ANXIOLYTIC DRUGS Propranolol and Exposure Therapy in the Treatment of Phobia Propranolol is a beta-blocker, traditionally used to treat conditions like hypertension and arrhythmias. In the context of psychiatry, propranolol is used in exposure therapy for the treatment of phobias and post-traumatic stress disorder (PTSD). How Propranolol Works in the Context of Fear and Anxiety Physical Symptoms: Propranolol can reduce the physical symptoms of anxiety, such as increased heart rate and tremors, by blocking the effects of adrenaline. Emotional Response: Evidence suggests that propranolol might influence the emotional component of memories during recall, potentially making it easier for individuals to engage with fear. Exposure Therapy A psychological approach aimed through gradual exposure to phobic imagery, systematically desensitises individuals to feared stimuli. A squiggle A picture of A video of a A toy spider A real spider Touching a representing a spider spider on hand in a tank real spider a spider Exposure therapy can also occur in a virtual reality environment Propranolol and Exposure Therapy in the Treatment of Phobia Reducing Physical Anxiety Symptoms: Propranolol may help patients engage more effectively in exposure therapy by reducing the physical symptoms of anxiety during the session. Decoupling: By mitigating the emotional response during the recall and confrontation of fear memories, propranolol can aid in “decoupling” the memory from the emotional and physical response typically associated with it. GABA THE MAJOR INHIBITORY NEUROTRANSMITTER IN THE BRAIN MOST INHIBITORY SYNAPSES IN THE BRAIN USE Y- AMINOBUTYRIC ACID (GABA) AS A NEUROTRANSMITTER.  GABA RECEPTORS The major inhibitory neurotransmitter, GABA, interacts with 2 major subtypes of receptor: PRESYNAPTIC GABAB GABAA receptors TERMINAL Found postsynaptically GABAB receptors Found presynaptically, and can inhibit synaptic release GABAA RECEPTORS MEDIATE INHIBITORY SYNAPTIC GABAA TRANSMISSION THROUGHOUT THE CNS. POSTSYNAPTIC DENDRITE  GABAA Receptors and Chloride Ions GABAA Receptors are permeable to Cl− ions Upon activation Cl− influx hyperpolarizes the membrane and inhibits action potentials. Electron micrograph of a GABAA receptor  GABAB Receptors and Seizures GABAB receptors are associated with second messenger systems rather than Cl− channels The second messenger systems often result in opening of K+ channels, leading to a hyperpolarizing current. The decreases GABA release and drugs which activate GABAB receptors can cause seizures  Behavioural Spectrum of GABAA Activation DECREASED GABA ACTIVITY INHIBITION OF THE GABA SYSTEM CAN INCREASE ANXIETY AND AT HIGHER LEVELS OF SEIZURES ACTIVATION CAN CAUSE SEIZURES DECREASING GABA ACTIVITY HIGH ANXIETY - PANIC SLIGHTLY DECREASED GABA INCREASED ANXIETY NORMAL GABA ACTIVITY Benzodiazepines Mechanism of Action Enhance the effect of the neurotransmitter GABA, leading to central nervous system depression. Examples Diazepam (Valium), lorazepam (Ativan), alprazolam (Xanax), and clonazepam (Klonopin).  Behavioural Spectrum of GABAA Activation NORMAL GABA ACTIVITY SLIGHTLY INCREASED GABA ACTIVITY ANTI-ANXIETY HIGH GABA ACTIVITY SEDATION HIGHER GABA ACTIVITY MARKED SEDATION SLEEP  Clinical Importance of GABAa Each of the five sub-units of the GABAA—benzodiazepine receptor complex is a different protein. These can be classified into families according to their structural similarities. The principal families have been coded the α, β and γ sub-units. GABA binds to the β sub-unit Clinical Importance of GABAa GABA ANTIANXIETY AND ANTICONVULSANT ANTI- INSOMNIA GENERAL ANESTHESIA Benzodiazepines As Rapid Onset Anxiolytics Benzodiazepines are used to treat acute anxiety. Those used to treat anxiety have a long biological half-life They are no longer used in long-term therapy BENZODIAZEPINES ARE OFTEN CO- ADMINISTERED DURING SSRI USE Benzodiazepines act on GABAA receptors Channel Modulators – Benzodiazepines Long-acting Benzodiazepines and Nordazepam Some long-acting agents (e.g. Diazepam and chlordiazepoxide) are converted to a long-lasting active metabolite (nordazepam). Nordazepam has a half-life of about 60 h This accounts for the tendency of many benzodiazepines to produce cumulative effects and long hangovers when they are given repeatedly.  Sedation Benzodiazepines Dizziness and Ataxia Adverse Effects Impaired coordination and balance Cognitive impairment Anterograde Amnesia Psychomotor slowing Motor impairment Dependence and withdrawal (with long-term use) Serious Withdrawal effects Tolerance (with long-term use) higher doses to achieve therapeutic effects Risk of overdose Especially with alcohol  Benzodiazepines act on GABAA receptors REDUCTION OF MUSCLE TONE SEDATION AND AND CO- ANTI- INDUCTION OF ORDINATION CONVULSANT SLEEP (MUSCLE EFFECT (ANTI- (SEDATIVE AND RELAXANT) SEIZURE) HYPNOTIC) INCREASING INCREASING DOSE DOSE REDUCTION OF ANTEROGRADE ANXIETY AMNESIA (ANXIOLYTIC) AND AGGRESSION 28 Benzodiazepine Classification By Duration LONG ACTING SHORT ACTING MEDIUM ACTING 1-3 DAYS 3-8 HRS 10-20 HRS Anxiety, Insomnia, Pre-op Seizures, Alcohol anxiety Anxiety withdrawal Triazolam (Halcion) Alprazolam (Xanax) Diazepam (Valium) Midazolam Lorazepam Chlordiazepoxide (Librium) Benzodiazepines – Therapeutic uses For Sleep disorders Benzodiazepines can be used, preferably SHORT ACTING for a short period to reduce sleep–induction time, 3-8 HRS to reduce number of awakenings Insomnia to increase duration of sleep Tolerance can develop Rebound insomnia can be an issue Rebound anxiety 30  BENZODIAZEPINE BINDING SITE SUBTYPES BZ1 (ω1) associated with α1 BZ2 (ω2) associated with the subunit of the GABAA receptor BZ1 BZ2 α2 and α3 subunits of the GABAA receptor BZ1 Sedative and hypnotic effect (BZ1) BZ2 Anxiolytic (mainly BZ2) Muscle relaxant (BZ2) and Anticonvulsant (BZ1)  Anticonvulsant (BZ2) Specific drug – Zolpidem No specific drugs Non specific drug – diazepam Non specific drug – diazepam Tolerance develops rapidly to Tolerance develops slowly to BZ1 BZ2  Key Z- Z-drugs Drugs Z-Drugs are Non-benzodiazepine Zolpidem hypnotics Primarily used for treating insomnia Mechanism and Uses Zopiclone 1.Acts on GABAA receptors 2.Prescribed for short-term insomnia Zaleplon Clinical Recommended for short-term use Notes Monitor for abuse potential  Benzodiazepine Overdose and Flumazenil It blocks FLUMAZENIL ACTS benzodiazepines AS A COMPETITIVE from binding ANTAGONIST AT (where they THE have an effect) BENZODIAZEPINE Flumazenil has BINDING SITE no effect by itself 33  FLUMAZENIL Flumazenil is indicated for the complete or partial reversal of the central sedative effects of benzodiazepines. It may be used For termination of hypnosedative effects in general anaesthesia For diagnosis and treatment of intoxications or overdose with benzodiazepines REUPTAKE INHIBITORS IN ANXIETY SSRIs (Selective Serotonin Reuptake Inhibitors) Most of these Useful in long- Control is agents actually term gradually make anxiety management achieved over worse at the of anxiety a 2–4-week start of disorders course. therapy. SNRIs (Serotonin- Norepinephrin e Reuptake Inhibitors) Initial effects of these drugs that develop over time with receptor desensitisation takes place to exert a longer-term anti-anxiety effect? REUPTAKE INHIBITORS IN ANXIETY  First-line in anxiety BOTH CAN BE COMBINED WHAT IS DEPRESSION? The central feature of depression is an unpleasant (dysphoric) mood present most of the day for a long period of time It is often accompanied by: Intense mental anguish Inability to experience pleasure (anhedonia) Generalised loss of interest Sometimes anger and irritability are present Vincent van Gogh, Sorrowing Old Man “At Eternity’s Gate” Van Gogh painted this two months before his death. Source: Wikimedia. TREATMENT OF MAJOR DEPRESSION The Monoamine Hypothesis of Major Depression Drugs which Block Reuptake of Monoamine Neurotransmitter Molecules from the Synaptic Cleft Serotonin Tricyclic noradrenaline antidepressants reuptake inhibitors (TCAs) (SNRIs) Norepinephrine- Selective serotonin Dopamine reuptake inhibitors Reuptake Inhibitors (SSRIs) (NDRIs)  PRESYNAPTIC NEUROTRANSMITTER REUPTAKE TERMINAL Specific transporter proteins remove most small-molecule neurotransmitters (or PRESYNAPTIC their metabolites) from TERMINAL the synaptic cleft Thus, delivering them back to the presynaptic terminal for reuse POSTSYNAPTIC  PRESYNAPTIC TricyclicAntidepressants Tricyclic antidepressants (TCAs) TERMINAL Mechanism of action for the therapeutic effects AT SEROTONERGIC AND NORADRENERGIC SYNAPSE Tricyclic antidepressants are able to block the transporter at serotonergic and PRESYNAPTIC noradrenergic synapse TERMINAL This leaves serotonin/ noradrenaline in the synaptic cleft for a longer period where they can activate the post synaptic receptors for longer IMIPRAMINE A TCA POSTSYNAPTIC  Tricyclic antidepressants (TCAs) Examples: Imipramine (Tofranil), amitriptyline (Elavil), nortriptyline (Pamelor). Mechanism of action for adverse effects: Antagonists at H1 receptors – Drowsiness and sedation Antagonists at Adrenergic α1 receptors – Postural Hypotension, Hypotension Antagonists at muscarinic receptors – dry mouth, confusion, memory impairments and blurred vision In overdose can cause cardiac arrhythmias With alcohol – effects of ethanol potentiated – severe respiratory depression  Tricyclic antidepressants (TCAs) Overdose Tricyclic antidepressants were the second commonest cause of fatal drug poisoning in the 1970s and 80s, in developed countries, accounting for 20-25% of fatal drug poisoning in the United Kingdom and United States. THE SINGER-SONGWRITER NICK Because of the risk associated with overdose, DRAKE WHO DIED FROM AN TCAs are less commonly prescribed as first-line OVERDOSE OF AMITRIPTYLINE treatments for depression. They may be used in specific situations or when The British Journal of Psychiatry Apr other treatments fail. 2010, 196 (5) 354-358; DOI: 10.1192/bjp.bp.109.070219 SEROTONIN NORADRENALINE Serotonin noradrenaline PRESYNAPTIC TERMINAL REUPTAKE INHIBITORS reuptake inhibitors (SNRIs) Serotonin noradrenaline reuptake inhibitors are able to AT SEROTONERGIC AND NORADRENERGIC SYNAPSE block the transporter at serotonergic and noradrenergic synapse PRESYNAPTIC TERMINAL This leaves serotonin/ noradrenaline in the synaptic cleft for a longer period where they can activate the post synaptic receptors for longer VENLAFAXINE, AN SNRI POSTSYNAPTIC  Serotonin noradrenaline reuptake inhibitors (SNRIs) Mechanism of Action: SNRIs inhibit the reuptake of both serotonin and norepinephrine, increasing the availability of both these neurotransmitters in the synaptic cleft. Examples: Venlafaxine (Effexor XR), duloxetine (Cymbalta), desvenlafaxine (Pristiq). How do they differ from TCAs? TCAs block the reuptake pumps for both serotonin and norepinephrine but are not particularly selective, affecting other neurotransmitter systems. SNRIs are designed to selectively inhibit the reuptake of serotonin and norepinephrine with with minimal interaction with other neurotransmitter systems. Selective SerotoninReuptake Selective Serotonin PRESYNAPTIC TERMINAL Reuptake Inhibitors Inhibitors (SSRIs) These transporters are highly specific AT SEROTONERGIC SYNAPSE Selective serotonin reuptake inhibitors block the transporter. PRESYNAPTIC This leaves serotonin in TERMINAL the synaptic cleft for a longer period where they can activate the post synaptic receptors for longer FLUOXETINE, AN SSRI POSTSYNAPTIC Selective Serotonin Reuptake Inhibitors (SSRIs) fluoxetine (Prozac) They have minimal inhibitory effects on sertraline (Zoloft) the noradrenergic transporter, nor paroxetine (Paxil) have blocking actions on citalopram (Celexa) adrenergic and cholinergic escitalopram (Lexapro) receptors  SELECTIVE SEROTONIN REUPTAKE INHIBITORS SSRIs are currently among the most commonly prescribed antidepressants due to their efficacy and favourable side effect profile compared to older antidepressants like TCAs. SSRIs are highly lipophilic. ◉ Fluoxetine has been identified as “minimally toxic in doses up The popularity of SSRIs stems largely to 1,500 mg” from their ease of use, safety in 1. Borys DJ, Setzer SC, Ling LJ, et al. Acute overdose, relative tolerability, cost and fluoxetine overdose: a report of 234 cases. Am broad spectrum of uses. J Emerg Medicine. 1992;10:115–120. SSRI/SNRIs and Suicidality IT WAS INDICATED THAT IN CHILDREN AND ADOLESCENTS THE RISK OF SUICIDALITY AND AGGRESSION DOUBLED Suicidality and aggression during antidepressant treatment: systematic review and meta-analyses based on clinical study reports BMJ 2016; 352 doi: http://dx.doi.org/10.1136/bmj.i65 (Published 27 January 2016)  SSRI DRUGS – ARE THEY EFFECTIVE? – CONCEPT Y AXIS – IMPROVEMENT IN DEPRESSIVE SYMPTOMS X-AXIS – INITIAL SEVERITY OF DEPRESSIVE SYMPTOMS (HAMILTON SCALE) in a meta-analysis of over 47 doi:10.1371/journal.pmed.0050045 Administration. PLoS Med 5(2): e45. A Meta-Analysis of Data Submitted to the Food and Drug TJ, et al. (2008) Initial Severity and Antidepressant Benefits: Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore clinical trials a substantial response to placebo is seen in moderately depressed groups there is no significant difference in studies between placebo and fluoxetine, until severely depressed patient range is reached (hrsd > 28) HOWEVER, SIGNIFICANCE DIFFERENCES REACHED IN SEVERELY DEPRESSED PATIENTS MAY BE PARTIALLY ATTRIBUTABLE TO A DECREASE IN RESPONSIVENESS TO PLACEBO, RATHER THAN AN INCREASE IN RESPONSIVENESS TO MEDICATION. Ranges of Uses of Selective Serotonin Reuptake Inhibitors (SSRIs): First-line for most depressive disorders: SSRIs are commonly the first choice in treating major depressive disorder Panic Disorder: SSRIs like paroxetine and fluoxetine are particularly effective. Obsessive-Compulsive Disorder (OCD): Fluoxetine, paroxetine, and sertraline are often prescribed. Bulimia Nervosa: Fluoxetine is the only SSRI approved for this eating disorder. Premenstrual Dysphoric Disorder: Certain SSRIs can be effective.  SSRI vs SNRI Choice of drug? Often drugs with different binding profiles will have different effects in a patient. For example, a more 5-HT selective drug might be more effective than a less selective drug in some individuals and vice versa Norepinephrine-Dopamine PRESYNAPTIC TERMINAL Reuptake Inhibitors (NDRIs) NDRIs Block the reuptake of norepinephrine and dopamine. AT NORADRENERGIC AND DOPAMINERGIC SYNAPSES Bupropion acts as a noradrenaline- dopamine reuptake inhibitor (NDRI) It does not have activity as a PRESYNAPTIC Serotonin reuptake inhibitor TERMINAL It is an effective antidepressant on its own and is used in cases of incomplete response to first-line SSRI antidepressants. Example: Bupropion (Wellbutrin) POSTSYNAPTIC  BUPROPION Bupropion is one of the most widely prescribed antidepressants Evidence indicates that it is effective in clinical depression Bupropion does not usually cause sexual dysfunction as do SSRIs Bupropion treatment also is not associated with the drowsiness or weight gain that may be produced by other antidepressants Uses a similar mechanism to cocaine but has far less efficacy  ENZYMATIC DEGRADATION PRESYNAPTIC TERMINAL After a neurotransmitter has been secreted into the synaptic cleft, it must be removed MAO MAO This occurs through the reuptake transporter This enables the postsynaptic cell to produce another synaptic event. Inside the presynaptic terminal neurotransmitters undergo degradation by specific enzymes, monoamine oxidase (MAO) POSTSYNAPTIC  MAOI PRESYNAPTIC TERMINAL Monoamine oxidase inhibitors block the enzyme MAO MAO This increases the concentration of monoamines (5HT & NA) in the presynaptic neuron PRESYNAPTIC TERMINAL And more is released into the synaptic cleft A higher [serotonin] or [noradrenaline] enables greater activation of serotonin and noradrenaline receptors POSTSYNAPTIC First-Generation MAOIs: Overview Mechanism of Action Irreversibly inhibit MAO-A & MAO-B Due to irreversible Enzyme activity recovery requires new synthesis inhibition, enzyme Examples inactivation is permanent— Isocarboxazid highlighting the importance Phenelzine of careful monitoring. Tranylcypromine Dietary Considerations Avoid tyramine-rich foods (e.g., aged cheese, cured meats) Drug Interactions Combined with other serotonergic drugs can lead to serotonin syndrome The discovery of newer reversible inhibitors that show isozyme selectivity has rekindled interest in this class of drug PHENELZINE NEWER REVERSIBLE COMMON MAOI DRUGS DO NOT DISTINGUISH INHIBITORS SHOW MAO-A BETWEEN THE TWO MAIN MAO ISOZYMES ISOZYME SELECTIVITY IRREVERSIBLE MAO-A HAS A SUBSTRATE PREFERENCE FOR 5- REVERSIBLE MAOI HT AND NORADRENALINE, AND IS THE INHIBITORS ARE DESIRED TARGET FOR THE ANTIDEPRESSANT MORE VERSATILE MAOIS. MOCLOBEMIDE MAO-B HAS A SUBSTRATE PREFERENCE FOR THEY ALLOW FOR PHENYLETHYLAMINE AND DOPAMINE. THIS BETTER DOSE / TARGET IS PROBLEMATIC RESPONSE PROFILES REVERSIBLE MAOI Second-Generation MAOIs (Reversible & Selective) Mechanism: These are often selective for MAO-A over MAO-B and bind the enzyme reversibly. This means the inhibition isn't permanent; the drug can associate and dissociate from the enzyme. As a result, once the drug is discontinued, the enzyme activity can return without waiting for the synthesis of new enzymes. Examples: Moclobemide is a well-known reversible inhibitor of MAO-A (RIMA). Dietary Restrictions limited Drug Interactions fewer  Ketamine Small clinical trials suggested that a single, intravenous, sub-anaesthetic dose of ketamine, a non-competitive NMDA channel blocker, Ketamine produces a rapid but short-lasting decrease in depressive symptoms lasting from a few hours up to 14 days Rapid Reduction in Suicidal Thoughts This is without the 3- to 4-week delay in onset of action seen with other antidepressant drugs  Esketamine (Spravato) is an FDA-approved Esketamine | IN CLINICAL USE nasal spray for treatment-resistant depression.  Electroconvulsive Therapy (ECT) ECT is highly effective against depression Electroconvulsive therapy (ECT) is administered with modern anesthesia is relatively medically safe It remains the single most effective intervention for the acute treatment of serious major depression. Despite having a terrible reputation Electroconvulsive therapy is used when from the past, ECT is actually quite patients with major depression fail to effective. respond to other medications – it is the This still is from the film “One Flew last in the line Over the Cuckoos nest” (1975)  TRANSCRANIAL MAGNETIC STIMULATION Transcranial Magnetic Stimulation (TMS) is a non- invasive neuromodulation technique that utilizes magnetic fields to stimulate specific areas of the brain. It involves placing a coil over the scalp, which generates a magnetic field that can influence neuronal activity in the targeted brain region.  TRANSCRANIAL MAGNETIC STIMULATION TMS has been approved for the treatment of MDD, particularly when patients do not respond to first-line pharmacological treatments (treatment-resistant depression). http://www.popsci.com/article/science/magnetic-brain- stimulation-may-trump-drugs-severe- depression?dom=PSC&loc=recent&lnk=1&con=magnetic-brain- stimulation-may-trump-drugs-for-severe-depression TRANSCRANIAL MAGNETIC STIMULATION FOR PATIENTS WITH DEPRESSION, Major Depressive Disorder TMS APPEARS TO PROVIDE Numerous studies and clinical trials SIGNIFICANT BENEFITS IN SHORT- have demonstrated the efficacy of TERM TREATMENT STUDIES. TMS in treating MDD, particularly in individuals who have not responded to antidepressant medications. Other Disorders The efficacy of TMS for treating conditions beyond MDD (like anxiety disorders, PTSD, or other mood disorders) is still under investigation with mixed results. SCHIZOPHRENIA Art painted by artist suffering from schizophrenia Bryan J. Charnley (1949-1991) Schizophrenia affects about 1% of the population. It predominantly affects young people The average age of onset is 18 in men and 25 in women. Bethlem Royal Hospital  Psychosis Psychosis, or loss of contact with reality, is manifested in a variety of mental or psychiatric disorders. It can be acute, caused by drugs or toxins It can be a chronic disorder Artist William Kurelek (1927-1977) produced while a patient at Maudsley Hospital in London.  Psychosis Psychosis is usually characterized by more than one symptom, such as difficulty in processing information disorganized thoughts distortion of reality delusions, hallucinations, incoherence catatonia aggressive or violent behaviour Artist with Schizophrenia Kurelek, William (1927-1977)  Schizophrenia Schizophrenia, is a chronic psychotic disorder The symptoms of schizophrenia are divided into three groups: 1. Cognitive symptoms It is important to recognise that every individual with schizophrenia may present 2. Positive symptoms differently, and not all individuals will experience all these symptoms. 3. Negative symptoms Treatment approaches often depend on the predominant symptoms and their severity.  schizophrenia Cognitive symptoms reduce ability to think clearly and to perform daily tasks Impaired Attention and Concentration Impaired Working Memory Impaired Executive Function Impaired Reasoning and Problem Solving  Schizophrenia POSITIVE SYMPTOMS MAY BE CHARACTERIZED BY EXAGGERATION OF NORMAL FUNCTION (E.G., AGITATION) INCOHERENT SPEECH HALLUCINATIONS DELUSIONS PARANOIA  Schizophrenia NEGATIVE SYMPTOMS ARE CHARACTERIZED BY A DECREASE OR LOSS IN FUNCTION AND MOTIVATION. A POVERTY OR SIMPLICITY OF SPEECH BLUNTED AFFECT POOR SELF-CARE SOCIAL WITHDRAWAL NEGATIVE SYMPTOMS TEND TO BE MORE CHRONIC AND PERSISTENT Classification of Antipsychotic Drugs BY MOST COMMONLY PRESCRIBED first-generation Chlorpromazine (‘typical’, ‘classical’ Haloperidol or ‘conventional’) Fluphenazine antipsychotics Risperidone second-generation Olanzapine (‘atypical’) Quetiapine Aripiprazole antipsychotics Clozapine  Antipsychotic Agents Mechanisms of Action There are five subtypes of dopamine receptors numbered D1 through D5. Typical antipsychotics block the D2 (dopaminergic) receptor  D1 D2 D4 5-HT2 TYPICAL ANTIPSYCHOTICS Chlorpromazine ++ +++ - ++ Haloperidol + +++ - +  Dopamine and Schizophrenia Hyperactivity of dopaminergic transmission in this pathway is hypothesized to contribute to the positive symptoms of schizophrenia, such as hallucinations and delusions. Antipsychotic drugs, which primarily block D2 dopamine receptors, can reduce these positive symptoms Adverse Effects of D2 Antagonists Dopaminergic pathways Extrapyramidal Syndrome – Pseudoparkinsonism Pseudoparkinsonism Stooped posture Shuffling gait Rigidity Bradykinesia Tremors at rest Pill-rolling motion of the hand Extrapyramidal Syndrome – Acute Dystonia Acute dystonia Facial grimacing Involuntary upward eye movement Muscle spasms of the tongue, face, neck, and back (back muscle spasms cause trunk to arch forward) Laryngeal spasms Akathisia Restless Trouble standing still Paces the floor Feet in constant motion, Rocking back and forth Extrapyramidal Syndrome – Tardive Dyskinesia 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  Hyperprolactinaemia Antipsychotic drugs binding to D2 receptors can increase prolactin secretion. This causes hyperprolactinemia. ◉ In males decreased libido and impotence gynecomastia ◉ In females: Amenorrhea (stopping menstruation) Infertility Typical Antipsychotic Drugs and EPS High-potency agents such as haloperidol and fluphenazine have a higher incidence of EPS, with reports indicating that up to 30% or more of patients may experience these symptoms, particularly at higher doses. Lower-potency agents like chlorpromazine and thioridazine have lower rates of EPS but are more likely to cause sedation and other side effects.  Atypical Antipsychotics Atypical antipsychotics are also known as Second Generation antipsychotic drugs Atypical antipsychotics are also termed Serotonin/Dopamine Antagonists These agents are usually D2 and D4-dopamine and 5-HT2A receptor antagonists  Atypical Antipsychotic Drugs and EPS Risperidone has a moderate risk of EPS, especially at higher doses (risperidone at doses >6 mg/day. Olanzapine has a lower EPS risk than risperidone, but it can occur, especially at higher doses. Quetiapine and clozapine are associated with very low EPS risk at commonly used doses. Aripiprazole has a unique mechanism of action as a partial agonist at dopamine receptors, which is associated with a low risk of EPS.  Typical Antipsychotics are less Atypical Antipsychotics prescribed Classification of antipsychotic drugs Distinction between first- and second- generation drugs is defined by: Receptor profile – where they bind Incidence of extrapyramidal side effects (less in second-generation group) Efficacy (specifically of clozapine) in ‘treatment-resistant’ group of patients Atypical efficacy against negative symptoms Atypical Antipsychotics – Common Adverse Effects Generally, have a lower risk of EPS compared to typical antipsychotics. Some, like olanzapine and clozapine, are associated with metabolic side effects like weight gain, diabetes, and dyslipidemia Why are Atypical Antipsychotics Better with EPS? Under normal conditions in the striatum dopamine from the nigrostriatal pathway inhibit GABAergic neurons. Under normal conditions in the striatum, 5-HT, through 5-HT2A receptors, activate GABAergic neurons. GABAergic Activation Causes EPS Nigrostriatal Dopaminergic Inhibits GABA Neurons − GABAergic Activation Causes EPS Why are Atypical Antipsychotics Better with EPS? Typical antipsychotics block dopamine (D2) receptors in the striatum which prevents inhibition of GABAergic neurons → GABAergic Activation Causes EPS Typical antipsychotics have no activity at the 5-HT2A receptors Nigrostriatal Dopaminergic Inhibits GABA Neurons − GABAergic Activation Causes EPS Why are Atypical Antipsychotics Better with EPS? Atypical antipsychotics block dopamine (D2) receptors to a lesser degree in the striatum which prevents inhibition of GABAergic neurons less → Less GABAergic Activation Causing EPS Atypical antipsychotics block 5-HT2A receptors. Removes activation of GABA neurons by 5-HT2A receptors Nigrostriatal Dopaminergic Inhibits GABA Neurons − GABAergic Activation Causes EPS Differences between Typical and Atypical Antipsychotic Drugs Typical or first generation antipsychotics Atypical or second generation antipsychotics Examples include haloperidol, chlorpromazine Examples include risperidone, olanzapine, Mechanism of action is blockade of D2 receptors Mechanism of action is blockade of multiple receptors including D2, 5HT2A, and others Cause extrapyramidal side effects such as tremors, Have lower risk of extrapyramidal side effects due to rigidity, and dystonia due to high D2 receptor lower D2 receptor blockade and 5-HT2A antagonism blockade Have higher risk of tardive dyskinesia with long term Have lower risk of tardive dyskinesia use Less effective for negative symptoms and cognitive More effective for negative symptoms and cognitive impairment impairment Associated with higher rates of weight gain and Associated with lower rates of weight gain and metabolic side effects metabolic side effects initially but risk increases with long term use Older drug class with established efficacy and safety Newer drug class with less long-term safety and profile efficacy data available Aripiprazole Aripiprazole is an atypical antipsychotic used for symptomatic management of psychosis in patients with schizophrenia and for acute manic episodes  Aripiprazole Aripiprazole is a partial agonist at the D2, D3 and 5HT-1a receptors and an antagonist at the 5HT-2a receptor. D2 ANTAGONISM CAUSES EPS 5HT2A ANTAGONISM INCREASE DA D2 PARTIAL AGONISM CAUSES VERY IN NIGROSTRIATAL PATHWAY MINOR EPS  Aripiprazole Aripiprazole stabilizes dopamine and serotonin within the nucleus accumbens, ventral tegmental area, and frontal cortex This results in the management of positive, negative, and cognitive symptoms in schizophrenia. It is thought that partial agonism of aripiprazole at D2 receptors may be responsible for the effective management of positive, negative, and D3 for cognitive symptoms of schizophrenia.  Aripiprazole has an improved side effect profile Aripiprazole has been shown to reduce improve decrease symptoms of cognitive reduce psychiatric tardive function – cardiovascular hospitalization dyskinesia Possibly via risk factors rates D3 partial WHY? agonism cariprazine The most effective second-generation antipsychotic for treating negative symptoms is the relatively new drug Cariprazine (2015)  Cariprazine Cariprazine is a partial agonist at the D2, D3 (with a higher affinity than aripiprazole) and 5HT-1a receptors. It is not an antagonist at the 5HT-2a receptor. D2 ANTAGONISM CAUSES EPS D2 PARTIAL AGONISM CAUSES VERY MINOR EPS Antipsychotic drugs have severe drawbacks Not all schizophrenic patients respond to drug therapy. The 30% of patients who do not respond are classed as ‘treatment resistant’ and present a major therapeutic problem It is recommended to try clozapine in patients who are resistant to other antipsychotic drugs Clozapine High affinity partial agonist at D4 INCIDENCE LOW EPS Low affinity partial agonist at D2 High affinity full antagonist at 5-HT2A and 5-HT2C Why isn’t clozapine first line? 1.Agranulocytosis: A potentially life-threatening reduction in white blood cells, particularly neutrophils (neutropenia). This risk necessitates regular blood monitoring. 2.Myocarditis and Cardiomyopathy: Inflammation of the heart muscle (myocarditis) and disease of the heart muscle (cardiomyopathy) can occur, especially early in treatment. 3.Metabolic Syndrome: This includes weight gain, hyperglycaemia, and dyslipidaemia, with an increased risk for diabetes and cardiovascular disease. Bipolar disorder Bipolar disorder involves swings between two moods, manic (euphoric) and depressive (dysphoric) Manic episodes may be preceded by or precede hypomania or a depressive episode Drugs used in Bipolar Disorder Treatment Goals: Prevent manic episodes Alleviate depressive symptoms Avoid rapid cycling DRUG TREATMENT OF BIPOLAR DISORDER A range of drugs are now used to control the mood swings characteristic of manic-depressive (bipolar) illness. Mood stabilizers are used to treat bipolar affective disorder. Mood Stabilizers – Lithium Lithium was the Lithium can help to first drug used to stop the cycling manage this between manic and disorder. depressed states It controls the flight Lithium is often of ideas and administered as hyperactivity. Lithium Carbonate DRUG TREATMENT OF BIPOLAR DISORDER Lithium Mood stabilizers are used prophylactically over long periods Beneficial effects take 3–4 weeks to develop DRUG TREATMENT OF BIPOLAR DISORDER Given in an acute attack, Lithium they are effective only in reducing mania, DRUG TREATMENT OF BIPOLAR DISORDER but not the depressive phase Lithium is administered daily for prevention of cycling  Mood Stabilizers – Lithium Lithium has a calming effect but may cause some memory loss and confusion. Patient compliance is often an issue However, if the person stops taking lithium, manic behaviour may return.  Lithium adverse effects and toxicity Normal dose nausea, vomiting and diarrhoea | weight gain | hair loss | tremor Toxic Dose Acute lithium toxicity results in various neurological effects, progressing from confusion and motor impairment to coma, convulsions and death  Lithium toxicity – prolonged treatment Serious renal tubular damage may occur, making it essential to monitor renal function regularly in lithium-treated patients Thyroid enlargement, sometimes associated with hypothyroidism  Antiepileptic Drugs Effective In Bipolar Disorder Carbamazepine, valproate and lamotrigine have fewer side effects than lithium and have proved CARBAMAZEPINE efficacious in the treatment of bipolar disorder. They are effective in preventing the cycling between manic and depressed states These drugs are also used CARBAMAZEPINE in treating epilepsy  SODIUM CHANNEL INHIBITORS Many antiepileptic drugs bind to channels in the deactivated state, Preventing them from returning to the resting state + − − + + − − + Thus, reducing the number of functional channels available to generate action potentials. +  CARBAMAZEPINE Carbamazepine stabilizes the inactivated state of voltage- gated sodium channels + − − + + − − + +  ATYPICAL ANTIPSYCHOTIC DRUGS Atypical antipsychotic drugs (e.g. olanzapine, risperidone) are second- generation drugs developed for the treatment of schizophrenia ◉ These agents are D2- dopamine and 5-HT2A ATYPICAL ANTIPSYCHOTICS receptor antagonists ◉ They are effective for treatment of mania NOT CYCLING ◉ The exact mechanism of action is unknown  Use of SSRIS and Bipolar Disorder SSRIS AND SNRIS CAN PRECIPITATE MANIA THIS CAN OCCUR IN PATIENTS WITH UNIPOLAR (MAJOR) DEPRESSION While SSRIs, SNRIs, and other antidepressants can be used in bipolar THIS CAN LEAD TO A MISDIAGNOSIS disorder, they are typically prescribed OF BIPOLAR DISORDER with caution due to the potential risk of inducing mania or hypomania, especially when used without a mood stabilizer or antipsychotic. RECOMMENDED STRATEGIES IN BIPOLAR DISORDER Antidepressant Monotherapy: High risk for inducing mania Not recommended as a standalone treatment Must be paired with mood stabilizers or antipsychotics Preferred Treatments: Mood stabilizers (e.g., Lamotrigine) Atypical antipsychotics (e.g., Aripiprazole) Role of SSRIs in Treatment: Used with caution - Always in combination with mood- stabilizing agents  BIBLIOGRAPHY These books were used in the preparation of this lecture