Schizophrenia: CNS Mechanisms & Treatment PDF

Schizophrenia Psychosis (schizophrenia): the patient is isolated from reality suffer from hallucination and delusion 1% from peoples suffer from it The hallucination may be auditory or visual Hallucination and Delusions always begin at twenties of the age or late twenties The...

Schizophrenia Psychosis (schizophrenia): the patient is isolated from reality suffer from hallucination and delusion 1% from peoples suffer from it The hallucination may be auditory or visual Hallucination and Delusions always begin at twenties of the age or late twenties The occurrence of schizophrenia is due to genetic factor and the onset of symptoms is affected by stress conditions The early onset of schizophrenia is usually associated with positive symptoms hyperactivity exaggerated in everything like hallucination delusions abnormal speech and thinking due to increase the level of dopamine in mesolimbic and mesocortex The late onset of schizophrenia is usually associated with negative symptoms reduction in activity the patient is isolated from people and loss of motivation then may be suicidal attempts due to deficiency of dopamine in mesocortex The negative symptoms may be in late stage or chronic state Theories of pathophysiology or biochemical changes in CNS that leads to schizophrenia 1 Dopamine theory (Monoamine theory): Increase the level of dopamine and action on D2 receptors in mesolimbic and mesocortex that leads to positive symptoms of schizophrenia Evidence of dopamine theory: Drug like amphetamine enters the neurons of dopamine serotonin and noradrenaline and stimulate their release (catecholamines) and cause increase the effect of dopamine that leads to euphoria and increase self confidence but when dopamine dose is increased may lead to symptoms like hallucination Levodopa (L-dopa) precursor of dopamine when it is converted to dopamine in brain and level of dopamine is increased and acts on D2 receptor in mesolimbic mesocortex may lead to visual and auditory hallucinations Over dose of Bromocriptine ergot alkaloid derivative D2 receptor agonist in mesolimbic mesocortex may lead to hallucination D2 blockers typical antipsychotics (first generation or traditional antipsychotics) treat positive symptoms of schizophrenia The more potent D2 blocking activity the more antipsychotic activity as haloperidol the most potent D2 blocker used as 2 injection in hospitals for aggressive positive symptoms and this the most strongest evidence for Dopamine theory (the first and oldest theory) Serotonin (5-Hydroxy tryptamine) theory: Increase the level of serotonin leads to hallucination and it has a regulatory function as it binds to 5-HT2a receptor on the presynaptic dopaminergic neurons in nigrostriatal pathway and mesocortex and inhibits dopamine release that leads to negative symptoms of schizophrenia Evidence of Serotonin theory: Lysergic acid diethylamide (LSD) drug in stamps 5-HT1a or 5- HT1c serotonin receptors agonist leads to auditory and visual hallucination (mainly) and this may cause death Risperidone drug (atypical or second generation antipsychotic) 5-HT2a antagonist treat symptoms Glutamate theory: Deficiency of glutamate and its receptors leads to schizophrenia and hallucination from autopsy of the brain of dead patient with schizophrenia showed that level of glutamate and its receptors is very low 3 Evidence of glutamate theory: Ketamine and Phencyclidine drugs NMDA receptor blockers are general anesthetic injection before surgery when NMDA receptor is blocked this lead to inhibition to NMDA receptor coupled ion channel and reduce Na+1 and Ca+2 influx this leads to hallucination like schizophrenia but this insufficient information because there is no drugs used to prove this theory Typical classic antipsychotic (First generation or Traditional antipsychotics): Phenothiazines derivatives: Chlorpromazine (The Godfather) Thioridazine (The most powerful antimuscarinic activity) Trifluoperazine Fluphenazine Another group: haloperidol the most potent one the most powerful D2 antagonist used as injection in hospitals They treat positive symptoms of schizophrenia and contraindicated in negative symptoms Pharmacodynamics: D2 blocking activity in several areas in the brain: 4 Mesolimbic Mesocortex : main mechanism blocking of D2 receptor in mesolimibic mesocortex is the antipsychotic effect to treat positive symptoms of schizophrenia but worsen the negative symptoms so they treat positive symptoms only Nigrostriatal pathway (Basal ganglia): blocking of D2 receptor in striatum leads to imbalance between dopamine and acetylcholine that leads to two types of motor disturbances acute extrapyramidal symptoms (EPS) in the same day of initiating the drug and chronic symptom tardive dyskinesia after weeks or months from initiation of the drug The EPS are parkinsonian syndrome like tremors even at rest rigidity bradykinesia (slow motion) akathisia (motor restlessness) dystonia (muscle spasm) and gait posture abnormality due to blocking D2 receptors in striatum that leads imbalance between dopamine and acetylcholine these symptoms make the patients refuse the drug so its treated by muscarinic blockers atropine derivatives like benztropine or trihexyphenidyl even that these drugs have a muscarinic blocking activity example thioridazine the most powerful antimuscarinic and has the lowest EPS but also atropine derivatives are given with it and the atropine derivative is associated with fever (no sweat) blurred vision increase intraocular pressure (contraindicated in glaucoma) dry mouth constipation and urinary retention (worsen prostate 5 hypertrophy in elderly patients) and tachycardia as the acute EPS are reversible and can be treated but chronic tardive dyskinesia (chronic muscle contraction in the upper part of the body like neck and jaw due to upregulation of D2 receptors in striatum ) is irreversible cannot be treated Anterior pituitary: blocking D2 receptor in the anterior pituitary cause prolactin release (hyperprolactinemia) that’s leads to galactorrhea amenorrhea and infertility (no FSH) in females and gynecomastia and impotence in males Chemoreceptor trigger zone (CTZ): blocking of D2 in CTZ area in midbrain not covered with blood brain barrier leads to antiemetic action prochlorperazine and cure hiccups chlorpromazine before or after surgery 5-HT2a blocking activity: less than atypical second generation antipsychotics D2 blocking activity >>>>> 5-HT2a blocking activity Alpha one blocking activity: postural hypotension and reflux tachycardia Muscarinic blocking activity: atropine adverse effects fever (no sweat) blurred vision increase intraocular pressure (contraindicated in glaucoma) dry mouth constipation and urinary retention (worsen prostate hypertrophy in elderly patients) and tachycardia like thioridazine 6 Histamine one blocking activity: sedation and drowsiness like promethazine mainly as antihistaminic not antipsychotic therapy Atypical antipsychotic (Second generation antipsychotics): Risperidone Clozapine Olanzapine Quetiapine Aripiprazole They treat both negative and positive symptoms (less effective than typical antipsychotics in positive symptoms) of schizophrenia Paharmacodynamics: 5-HT2a blocking activity: main mechanism more than typical antipsychotics blocking of 5-HT2a in presynaptic dopaminergic neurons in mesocortex leads to increase release of dopamine chronically and improvement of the negative symptoms this blocking activity is the rational of atypical antipsychotics metabolic adverse effects like weight gain and abnormal levels of glucose and cholesterol in the blood 7 D2 blocking activity: in mesolimbic that leads to treatment of positive symptoms of schizophrenia and also work minimally in the other dopamine areas but not like typical antipsychotics associated with less extrapyramidal adverse effects due to:  Blocks 5-HT2a activity >>>>>> D2 blocking activity  Some of them have selective blocking of D2 receptor in mesolimbic mesocortex rather than D2 in striatum  Some of them dont block D2 receptor like quetiapine  Blocking of 5-HT2a in presynaptic dopaminergic neuron in nigrostriatal pathway leads to increase dopamine release in the striatum and restore the balance between acetylcholine and dopamine  Airipiprazole has 5-HT2a blocking activity in presynaptic dopaminergic neuron in nigrostriatal pathway that leads to increase dopamine release in the striatum and it is partial D2 receptor agonist in the striatum (not pure antagonist) this restore the balance between acetylcholine and dopamine 5-HT2a blocking activity >>>>> D2 blocking activity Alpha one blocking activity: minor less than typical antipsychotics Muscarinic blocking activity: minor less than typical antipsychotics 8 Histamine one blocking activity: minor less than typical antipsychotics Clinical treatment of schizophrenia: Antipsychotic drugs used to relieve symptoms forever but schizophrenia isn’t cured The clinical benefit appears after two or three weeks from initiation of the antipsychotic drug like antidepressants Risperidone is the first choice all over the world Aripiprazole is widely used in Egypt for treatment of negative symptoms of schizophrenia due to its blocking activity to 5- HT2a in presynaptic dopaminergic neuron in mesocortex that leads to increase dopamine release and it is partial agonist on D2 receptor in mesocortex (not pure antagonist) and it has less extrapyramidal side effects due to it is 5-HT2a blocking activity in presynaptic dopaminergic neuron in nigrostriatal pathway that leads to increase dopamine release in the striatum and its partial D2 receptor agonist in the striatum (not pure antagonist) this restore the balance between acetylcholine and dopamine and used for treatment of positive symptoms of schizophrenia due to its antagonistic activity on D2 receptor in mesolimbic due to slow dissociation from the receptor 9 Clozapine is reserved for refractory cases as it causes fatal neutropenia agranulocytosis and bone marrow suppression for 2% of patients and regular CBC should be monitored Typical antipsychotics are used when positive symptoms are aggressive and uncontrolled due to harmful effects of them Haloperidol is the most potent D2 blocker used as injection in hospitals for aggressive positive symptoms as D2 receptor is blocked in the same day of taking the drug but the onset of action begins after two weeks or three weeks and during this period the patient receives Electroconvulsive therapy for immediate improvement until the onset of D2 blocker begins the Electroconvulsive therapy is stopped The most dangerous side effect of typical antipsychotics is EPS that may make patients refuse the drug so muscarinic blockers atropine derivatives like benztropine or trihexyphenidyl should be used with typical or atypical antipsychotics These drugs may cause malignant hyperthermia 10: 15% from patients (strong muscle contraction associated with fever due to high stored Ca+2 that leads increase Ca+2 release) the basic treatment is cold ice water and Dantrolene Other clinical uses of antipsychotics: In both psychic and bipolar depression (manic depression) and sometimes in Autism 10  Parkinson’s Disease Progressive neurodegenerative disease of dopaminergic neurons in the nigrostriatal pathway (basal ganglia) that leads to motor disturbances like tremors (peripherally specially in fingers at rest and increase at stress) muscle rigidity (no flexibility in movement) bradykinesia (slow motion) and gait posture abnormality specially at the initiation of the gait These symptoms appear after the neurodegeneration of 80% or more of the nigrostriatal dopaminergic neurons after the age of 60 to 65 years old Neurodegenration means destruction of the neuronal structure and disappear of it or neuronal structure intact but the neuron not functioning It’s the second most common neurodegenerative disease after Alzheimer’s disease in the world Pathophysiology: Neurodegenration of dopaminergic neurons in basal ganglia (nigrostriatal pathway or extrapyramidal system) that originate from substantia nigra and release dopamine in the striataum that’s responsible for motor function Neurodegeneration of the nigrostriatal dopaminergic neurons in basal ganglia leads to imbalance between excitatory acetylcholine (works on muscarinic receptor) and inhibitory 11 dopamine (works on D2 receptor) neurotansmitters that leads increase acetylcholine effect not level reduce dopamine effect and tremors rigidity bradykinesia and gait posture abnormality other symptoms like dyskinesia (rapid irregular movement) akathisia (muscle restlessness) dystonia (muscle spasm) These symptoms appear after the neurodegeneration of 80% or more of nigrostriatal dopaminergic neurons at the age of 60:70 years old and associated with non-motor symptoms like mask face and types of dementia in late ages Primary parkinsonism (parkinsonian disease) It is idiopathic neurodegeneration of nigrostriatal dopaminergic neurons It may be due to oxidative stress free radicals oxidizing agents damage the neurons (antioxidant prevent free radicals like vitamins and GSH) Dopamine when metabolized by MAO-B it is converted to free radical metabolite damage the neurons so MAO-B inhibitors drugs have dual function increase dopamine level and prevent its conversion to toxic free radical metabolite Secondary parkinsonism (parkinsonian syndrome) No neurodegeneration occurs but symptoms only due to 12   Drugs induced like antipsychotics D2 receptor antagonist or reserpine that depletes dopamine stores symptoms is reversible if stop the drugs  Chemical induced like carbon monoxide (CO) manganese and MPTP methyl-phenyl-tetrehydropyridine  Pesticides like rotenone or paraquat  Infection induced viral encephalitis Aim of the therapy: The aim of therapy is to restore the balance between dopamine and acetylcholine as increase dopamine or reduce acetylcholine or both to treat tremors rigidity bradykinesia and gait posture abnormality Parkinsonism Drugs:  Antimuscarinic drugs  Levodopa (L-dopa) and its combinations with carbidopa or benserazide  Dopamine (D2) agonist  MAO-B inhibitors  COMT inhibitors Only L-dopa combinations and D2 agonist are major therapy and others are adjuvant therapy 13 These drugs are taken forever to relieve the symptoms but neurodegeneration of nigrostriatal dopaminergic neurons is progressive Antimuscarinics drugs: Benztropine or trihexyphenidyl Advantages: treat tremors and rigidity only not treat bradykinesia nor gait posture abnormality Disadvantages: atropine adverse effects fever (no sweat) blurred vision increase intraocular pressure (contraindicated in glaucoma) dry mouth constipation and urinary retention (worsen prostate hypertrophy in elderly patients) and tachycardia Blocking of muscarinic receptor isn’t considered treatment for parkinsonism Only adjuvant therapy for parkinsonism and they reduce EPS associated with antipsychotics Dopamine drugs: L-dopa or D2 agonist Advantages: treat tremors rigidity bradykinesia and gait posture abnormality 14 As bradykinesia (slow motion) may be converted to dyskinesia (rapid irregular movement) Disadvantages: peripheral and central side effects Peripheral side effects:  Nausea vomiting and anorexia due to agonistic activity of dopamine drugs on D2 receptors in CTZ (not covered with BBB) domperidone is used manage this as it blocks D2 receptor in CTZ without passing BBB so its suitable for Parkinsons disease unlike metoclopramide that block D2 receptor in CTZ and pass BBB and block D2 receptor in striatum and worsen Parkinson’s disease  Cardiac dysrhythmia due to structural similarity between noradrenaline and dopamine drugs (even L-dopa will be converted by peripheral L-dopa decarboxylase peripherally to dopamine) as they have affinity to B1 receptor in the heart  Postural hypotension and reflux tachycardia due to venodilating effect of dopamine drugs mainly as they reduce venous return to heart then reduce cardiac output that leads to postural hypotension and reflux tachycardia and minimally they reduce renin and NA release 15 Central CNS side effects:  Psychotic symptoms like hallucination and delusions the most dangerous that may lead to stop the drug as dopamine drugs not activate D2 receptor in the striatum only they also activate D2 receptors in mesolimbic too  Dyskinesia due to activity of Dopamine drugs on D2 receptors in striatum as bradykinesia become dyskinesia Psychotic symptoms mainly present with D2 agonist but also present with L-dopa Dyskinesia mainly present with L-dopa but also present with D2 agonist Peripheral side effects almostly the same L-dopa: The discovery of Dopamine drugs pass through many steps first trial dopamine IV infusion but there is no benefit as dopamine doesn’t cross BBB then L-dopa precursor of dopamine is used this lipophilic and pass BBB then enter the brain and nigrostriatal dopaminergic neuron to be converted to dopamine by L-dopa decarboxylase and treat tremors rigidity bradykinesia and gait posture abnormality but the disadvantages this drug depends on the 20% remain of nigrostriatal dopaminergic neurons and the neurodegeneration is progressive. It has peripheral and central side effects and 16 only 1:3% of dose reach the brain some of it lost in GIT and be converted by peripheral L-dopa decarboxylase to dopamine before reaching the brain this lead to peripheral side effects. to increase the amount of L-dopa that reach the brain the dose was increased but this worsen the peripheral side effects to solve the peripheral side effects L-dopa was given with peripheral L-dopa decarboxylase inhibitor not pass BBB like carbidopa or benserazide this increase level of L-dopa that reach the brain from 3% to 10% reduce the dose of L-dopa to 25% from the dose without carbidopa and this reduce the peripheral side effects and cost Notes:  there is problem in L-dopa absorption in GIT like amino acids as it needs carrier to be absorbed to the blood if protein is taken with L-dopa the protein will be broken to amino acids and compete with L-dopa for carrier to be absorbed to the blood and this reduce the absorption of L- dopa so it should be taken on empty stomach or one hour before the food  L-dopa is converted to dopamine by L-dopa decarboxylase and vitamin B6 is coenzyme for L-dopa decarboxylase when patients take vitamin B6 with L-dopa this potentiate the peripheral conversion of L-dopa to dopamine and increase peripheral side effects so L-dopa is 17  contraindicated with vitamin B6 unless carbidopa is taken with L-dopa no problem After 5:10 years from initiation of L-dopa and carbidopa some types of fluctuation of response occurs like Wearing off phenomenon (end of dose Akinesia or effect): The t1/2 of L-dopa with carbidopa combination is 2 hours but it is taken 3 times daily due to the 20% remain of nigrostriatal dopaminergic neurons as it is converted in it to dopamine and stored to cover the remain period. In this phenomenon after 2 hours of taking the combination the symptoms relapse due to further neurodegeneration of the remain 20% of nigrostriatal dopaminergic neurons to solve this problem we may take the combination every 2 hours but this associated with adverse effects and high cost (not applicable) the real solution is to add COMT (enzyme in periphery and CNS) inhibitors to combination entacapone it is peripheral COMT inhibitor prevent peripheral metabolism of L-dopa to 3-OMD before reaching the brain this increase the level of L-dopa that reachs the brain as the solution of wearing off phenomenon taking L-dopa + Carbidopa + Entacapone Another drug Tolcapone inhibits both central and peripheral COMT but it is associated with hepatotoxicity so entacapone is more common 18 After years from wearing off phenomenon on/off phenomenon occurs ON/OFF phenomenon: when taking the drug sometimes relieve the symptoms well as bradykinesia may be dyskinesia and sometimes not relieve the symptoms due to further progression of neurodegeneration to solve this problem we add Apomorphine Sc D2 agonist in off period then after years with progressive neurodegenration the drugs not relieve symptoms off off off we conclude that the remain 20% of nigrostriatal dopaminergic neurons are lost and initiate D2 agonist and some doctors initiate D2 agonist at the beginning of ON/OFF phenomenon Some doctors initiate D2 agonist at the diagnosis of parkinsonism but logically stepwise L-dopa should be initiated at the diagnosis then after 20% remain of nigrostriatal dopaminergic neurons are lost we initiate D2 agonist L-dopa is more effective than D2 agonist to control parkinsonism but the choice of the drug is according to the side effects Psychotic symptoms hallucination and delusions (the most dangerous) side effects are more severe with D2 agonist than L- dopa 19 Dyskinesia side effect is more severe with L-dopa than D2 agonist If the patient has high risk of psychotic symptoms L-dopa should be initiated If the patient has high risk of dyskinesia D2 agonist should be initiated D2 agonsit: Bromocriptine: ergot alkaloid (vasoconstrictor) contraindicated in peripheral vascular disease pulmonary fibrosis and retroperitoneal fibrosis Pramipexole: better than bromocriptine not associated with vasoconstriction nor pulmonary fibrosis nor elevating blood pressure Apomorphine: used as Sc in off period of on/off phenomenon Monoamine oxidase inhibitors(MAO-inhibitors): Monoamine oxidase enzyme presents inside the cytoplasm of neuron in mitochondria that’s responsible for neurotransmitter metabolism There are two types of MAO: MAO-A: responsible for NA serotonin and tyramine metabolism MAO-B: responsible for dopamine metabolism 20 The drugs that selectively inhibit MAO-A treat depression and drugs that selectively inhibit MAO-B treat parkinsonism Some drugs non-selectively inhibit MAO Drug food interaction: Tyramine containing food like old and Roquefort cheese beer and Egyptian mesh cause increase NA release if MAO-A (responsible for NA and tyramine metabolism) is inhibited the tyramine will not be metabolized and the level of NA will be increased this leads to hypertensive crisis hemorrhage in the brain and death MAO-B inhibitors: Selegiline and rasagiline selective irreversible inhibition to MAO-B only They used as adjuvant therapy for parkinsonism as they inhibit dopamine metabolism that leads to increase in dopamine level and prevent dopamine metabolism to toxic free radical metabolite It depends on the 20% remain of nigrostriatal dopaminergic neurons No problem with tyramine containing food If we increase the dose of the selective MAO-B inhibitor it will lose its selectivity 21 Selegiline is metabolized to methamphetamine may lead to insomnia and delusion Amantadine: Antiviral drug used as adjuvant in the treatment of parkinsonism as it promotes dopamine release inhibits dopamine uptake and blocks muscarinic receptor It depends on the 20% remain of nigrostriatal dopaminergic neurons It is associated with tolerance so the dose should be increased Notes: L-dopa and its combination (with carbidopa or benserazide) or D2 agonist are the major therapy Other drugs are adjuvant to them L-dopa MAO-B inhibitors and amantadine depend on the 20% remain of nigrostriatal dopaminergic neurons and when neurons are lost D2 agonist is effective 22  Depression Depression is two types classic unipolar depression and bipolar depression Classic Unipolar Depression (psychic depression): It is mood disorder characterized by persistent sadness hopelessness may last 2 weeks or more and loss of interest to normal activities then disturbance in the pattern of sleeping and appetite and may lead to suicidal attemps Bipolar Manic Depression: It is associated with two phases. The first phase (depressed phase) patients suffer from sadness hopelessness and the second phase (manic phase) patients have high self-confidence as guide persons and hyperactivity Theories of pathophysiology or biochemical changes in CNS that leads to unipolar depression Monoamine theory: Psychic depression is due to deficiency of noradrenaline (NA) or serotonin 5-Hydroxytryptamine (5-HT) or both in the brain (the oldest theory) 23 Evidence of Monoamine theory: When reserpine drug is taken that depletes NA serotonin and dopamine (not important in depression) stores the depression occurs as chronic reserpine intake will induce depression after 5:10 years When tricyclic antidepressants TCAs (prevent reuptake1 of NA mainly and serotonin) or selective serotonin reuptake inhibitors SSRIs (prevent the reuptake of serotonin) the depression is treated due to the increase in the level of NA or serotonin or both in the brain If patient who is treated by SSRIs take tryptophan (precursor of serotonin) free diet the depression relapse and this is the proof of serotonin importance in depression If patient who is treated by TCAs take tryptophan (precursor of serotonin) free diet the depression not strongly relapse as TCAs prevent mainly the reuptake of NA If patient who is treated by TCAs take drug that prevents NA synthesis or depletes NA stores the depression relapse and this is the proof of NA importance in depression Drawbacks of Monoamine theory: When we take SSRIs the level of serotonin increase in the same day or when we take TCAs the level of NA or serotonin or both increase in the same day but the depression is treated after 2 24 weeks this indicate that increase the level of NA and serotonin is first step in the treatment and the brain will make protein substance brain derived neurotrophic factor (BDNF) in this 2 weeks that helps in the treatment Brain Neurotrophic theory: From the previous theory it was discovered that brain makes protein substance brain derived neurotrophic factor (BDNF) that’s responsible for neuronal health survival safety growth (neurogenesis) neuronal connection and elasticity and BDNF level decrease in the brain in depression so deficiency of BDNF in the brain leads to psychic depression Evidence of Brain Neurotrophic theory: Taking antidepressant drugs that increase level of NA or serotonin or both will increase BDNF level after 2 weeks and treat depression as these drugs increase the level of NA and serotonin in brain at the same day this lead the brain to make BDNF and the synthesis of BDNF by brain takes 2 weeks after BDNF being synthesized the depression will be treated BDNF is important in hippocampus (mainly) and cortex as it is shown that hippocampus volume is reduced in depressed patient and when antidepressant drug is given that increase BDNF after 2 weeks the hippocampus volume returns to normal 25 as there is relationship between BDNF level hippocampus volume and depression Direct infusion of BDNF in the hippocampus or midbrain of experimentally induced depressed rats treat depression Pain and stress reduce BDNF level in the brain Hormonal theory: Hormonal disturbance may lead to depression Cortisol has anti-stress effect and it is secretion increase in the morning as sunlight increases CRH (corticotrophin releasing hormone) and ACTH (adrenocorticotrophic hormone) then adrenal cortex secrets cortisol as in experimental rats the adrenal cortex was removed and rats were susceptible to stress then rats were given cortisone and the stress was reduced so cortisone has anti-stress activity but the increase in CRH or ACTH or cortisol leads to disturbance in hypothalamic pituitary adrenal cortex axes that leads to reduction in BDNF and depression and when cortisone binds to its receptor in hippocampus reduces BDNF synthesis and induces depression Thyroxine deficiency induces depression Testosterone deficiency in males induces depression 26 Estrogen deficiency in females leads to depression as in postmenopausal women when ovaries don’t produce estrogen and progesterone this induce psychic depression These are the oldest three and main theories of depression some modern theories like glutamate theory and melatonin theory but the monoamine theory and brain neurotrophic theory are the most important Aim of the therapy of unipolar depression: According to monoamine theory the level of NA or serotonin or both should be increased. In normal nerve the synthesis of neurotransmitter like serotonin or NA occurs then it is stored to be to be protected from metabolism by MAO-A in cytoplasm then release from presynaptic cleft to synapse and binds to receptor then dissociates from receptor and the reuptake occurs by transporter back to presynaptic cleft to be metabolized by MAO-A or stored again so the drugs prevent reuptake or metabolism of NA or serotonin or both and the release isn’t target of drugs because only amphetamine can promote the release of NA serotonin and dopamine but it isn’t used due to it is harmful side effects like addiction and psychosis and the treatment mainly by the drugs that prevent the reuptake after 2 weeks from initiation 27 Drugs prevent reuptake: Tricyclic antidepressants TCAs Selective serotonin reuptake inhibitors SSRIs Serotonin norepinephrine reuptake inhibitors SNRIs Selective norepinephrine reuptake inhibitors Drugs prevent metabolism: Selective MAO-A inhibitors and nonselective MAO inhibitors Atypical drugs: Work by different mechanisms and treat depression Tricyclic antidepressants TCAs: Imipramine Desipramine Amitriptyline Nortriptyline Pharmacodynapmics: They prevent reuptake1 of NA or serotonin or both so they treat depression after 2 weeks as in depression the level of NA and serotonin decrease below the normal and TCAs raise the level of NA and serotonin to normal but if NA level is raised to 28 high level above the normal this lead to CNS excitation and agitation Alpha one blocking activity: postural hypotension and reflux tachycardia Muscarinic blocking activity: atropine adverse effects fever (no sweat) blurred vision increase intraocular pressure (contraindicated in glaucoma) dry mouth constipation and urinary retention (worsen prostate hypertrophy in elderly patients) and tachycardia but due to muscarinic blocking activity imipramine is used for nocturnal enuresis in children Histamine one blocking activity: sedation and drowsiness like first generation antihistamines Clinical uses: Antidepressant after 2 weeks Anxiolytic after 2 weeks Neuropathic pain specially amitriptyline Prophylactic against migraine specially amitriptyline Nocturnal enuresis in children specially imipramine These drugs aren’t first line in depression they used in neuropathic pain and used in depression when the sedative 29 action is required due to H1 blocking activity if the patient is agitated or the depressed patient has neuropathic pain The tachycardia is duplicated with TCAs like typical antipsychotics due to muscarinic blocking activity and alpha one blocking activity (postural hypotension and reflux tachycardia) The most dangerous event in TCAs is cardiac arrhythmia due to high level of NA not induce arrhythmia but it is contraindicated if the patient suffers from heart problems Selective serotonin reuptake inhibitors SSRIs: Escitalopram Sertraline Fluoxetine Paroxetine Pharmacodynamics: They prevent reuptake1 of serotonin so they are first line in depression They don’t affect the NA level so no problem with cardiac arrhythmia Very weak blocking activity of muscarinic histamine and alpha 1 receptors so they aren’t associated with atropine side effects 30 like dry mouth urinary retention and constipation nor postural hypotension nor reflux tachycardia nor sedation Clinical uses: Antidepressant first line after 2 weeks Anxiolytic after 2 weeks Neuropathic pain Feeding disorder like anorexia nervosa and bulimia nervosa specially Fluoxetine The most dangerous side effect is sexual dysfunction as SSRIs reduce sexual desire and cause retardation in ejaculation (most important) in men when serotonin level increase in the brain so SSRIs used in premature ejaculation Men use dapoxetine SSRI (alternative to tramadol) for premature ejaculation not used as antidepressant Tramadol: Mu2 receptor agonist analgesic effect and prevent reuptake of NA and serotonin like antidepressant it elevates the mood and increases self confidence so persons who work in jobs that require physical efforts as they work 18 hours take tramadol to help them but this associated with addiction and men use tramadol for premature ejaculation as it increases serotonin level in brain but dapoxetine prevent reuptake of 31 serotonin and cause retardation in ejaculation without addiction SSRI shouldn’t be taken MAO inhibitors as both of them increase serotonin level in the brain that leads to fatal serotonin syndrome (massive level of serotonin in the brain) which is characterized by hyperactivity in muscles then convulsion and hyperthermia finally reduce mental status and death so it shouldn’t be taken together even If the doctor wants to change SSRIs with MAO inhibitors or vice versa he should wait the wash out period of the first drug before initiating the another one to prevent fatal serotonin syndrome Serotonin norepinephrine reuptake inhibitors SNRIs: Venlafaxine Duloxetine Pharmacodynamics: They prevent reuptake of serotonin (mainly) and NA (minimally) No blocking activity of muscarinic histamine and alpha 1 receptors so they aren’t associated with atropine side effects like dry mouth urinary retention and constipation nor postural hypotension nor reflux tachycardia nor sedation 32 Clinical uses: Antidepressant after 2 weeks Anxiolytic after 2 weeks Neuropathic pain as it is the main use of Serotonin norepinephrine reuptake inhibitors SNRIs (first line in the world in neuropathic pain) Neuropathic pain: It is characterized by pain inflammation and numbness in the nerves like diabetic neuropathy NSAIDs may be not useful in neuropathic pain First line in the world are antidepressants for neuropathic pain venlafaxine then duloxetine then amitriptyline (TCAs) as venlafaxine or duloxetine treat anxiety or depression that may be associated with neuropathic pain and amitriptyline used if the sedative effect of it is needed due to its blocking activity to H1 receptor Venlafaxine is associated with tachycardia and increasing blood pressure Duloxetine is associated with hepatotoxicity as it isn’t induce hepatotoxicity but it is contraindicated in liver disease 33 If patient suffers from high BP or tachycardia duloxetine is initiated If patient suffers from liver disease venlafaxine is initiated If patient suffers from high BP or tachycardia and liver disease amitriptyline is initiated If patient suffers from sedation and atropine side effects of amitriptyline go to the second line Second line antiepileptic drugs like pregabalin and gabapentin they antagonize glutamate in the brain and associated with addiction Third line local anesthetics tramadol then opioids like meperidine and pethidine Selective norepinephrine reuptake inhibitors: Bupropion Atomoxetine Pharmacodynamics: They prevent reuptake of NA only No blocking activity of muscarinic histamine and alpha 1 receptors only TCAs have strong blocking activity to them 34 Clinical uses: Antidepressant anxiolytic and neuropathic pain but the clinically uses of them are other things Bupropion: for smoking cessation Atomoxetine: like the uses of amphetamine without its harmful effects like addiction and psychotic symptoms hallucination and delusions as it is used in Attention deficit hyperactivity disorder ADHD (due to loss of dopaminergic and noradrenergic neurons) as amphetamine increase the release of NA serotonin and dopamine that leads psychotic problems and addiction but Atomoxetine increase NA level only so it isn’t associated with psychotic problems and addiction Narcolepsy (stimulant due to NA) Obesity (due to anorexigenic effect) Note: amphetamine derivatives methamphetamine dextroamphetamine and methylphenidate have antidepressant activity and other uses of amphetamines but they aren’t used due to their harmful effects like tolerance addiction hallucination and urinary retention 35 Drugs prevent metabolism: Monoamine oxidase inhibitors (MAO inhibitors): Monoamine oxidase enzyme presents inside the cytoplasm of neuron in mitochondria that’s responsible for neurotransmitter metabolism There are two types of MAO: MAO-A: responsible for NA serotonin and tyramine metabolism MAO-B: responsible for dopamine metabolism The drugs that selectively inhibit MAO-A treat depression and drugs that selectively inhibit MAO-B treat parkinsonism Some drugs non-selectively inhibit MAO Non selective irreversible MAO inhibitors: Phenelzine binds to MAO-A and MAO-B by covalent bond and inhibits both of them and the body should synthesize new enzyme and this may last 2 weeks or more so it has long duration of action if it is used in depression as after stopping the drug its effect may remain 2 weeks or more Selective reversible MAO-A inhibitors: Moclobemide inhibits NA metabolism so NA release in high amount and treats depression 36 They used as antidepressant and anxiolytics after 2 weeks but non-significant benefit in neuropathic pain These drugs are very effective but they aren’t used due to Side effects: atropine actions like dry mouth and postural hypotension Drug drug interaction and drug food interaction like SSRI shouldn’t be taken MAO inhibitors as both of them increase serotonin level in the brain that leads to fatal serotonin syndrome (massive level of serotonin in the brain) which is characterized by hyperactivity in muscles then convulsion and hyperthermia finally reduce mental status and death so it shouldn’t be taken together even If the doctor wants to change SSRIs with MAO inhibitors or vice versa he should wait the wash out period of the first drug before initiating the another one to prevent fatal serotonin syndrome Tyramine containing food like old and Roquefort cheese beer and Egyptian mesh cause increase NA release if MAO-A (responsible for NA and tyramine metabolism) is inhibited the tyramine will not be metabolized and the level of NA will be increased that leads to hypertensive crisis hemorrhage in the brain and death 37 Atypical drugs: Trazodone - Mirtazpine They work by different mechanisms and treat depression Trazodone: blocks 5-HT2 and slightly prevents serotonin reuptake so it treats depression after 2 weeks Mirtazpine: block 5-HT2 receptor and alpha 2 receptor in presynaptic nerve that leads to release of NA and treat depression after 2 weeks They have strong H1 blocking activity and they are used mainly as sedative hypnotics to help depressed patient to sleep Treatment of Bipolar manic depression: Lithium is the best drug to treat bipolar manic depression but it isn’t used due to it is narrow therapeutic index so it is calculated by milliequivalent (mEq) in the blood and it is toxicity as  It concentrates in thyroid gland and cause impairing thyroid hormone synthesis that leads to hypothyroidism  It reduces antidiuretic hormone (ADH) that leads to polyuria polydipsia (diabetes insipidus)  It causes tremors anorexia nausea vomiting and diarrhea If the Lithium is used the level of it in the blood should be monitored every 2 months to adjust the dose due to it is toxicity 38 Antiepileptic drugs like lamotrigine carbamazepine and valproate are alternatives to Lithium but these drugs are less effective than Lithium but more safe than it Notes: Antidepressant drugs aren’t used forever only period of time until remission Antidepressant drugs have several uses like:  Anxiolytics after two weeks (antidepressants are better than benzodiazepine derivatives due to their side effects like sedation drowsiness muscle relaxation withdrawal symptoms and addiction at the long run so doctors initiate both benzodiazepine derivatives and antidepressants after 2 weeks when the anxiolytic effect of antidepressants starts benzodiazepine derivative is stopped)  Neuropathic pain (the antidepressants venlafaxine duloxetine and amitriptyline are first line in neuropathic pain in the world)  Nocturnal enuresis in children specially imipramine  Feeding disorder like anorexia nervosa and bulimia nervosa specially Fluoxetine  Prophylactic against migraine specially amitriptyline 39