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MPHRM-512 Lec-7 V-3-Date Antipsychotics

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1 MPHRM-512 Lec-7 V-3-Date-8-11-14 Antipsychotics
Psychotropic drugs are those having primary effects on Psyche (mental) and are used for treatment of psychosis.

2 Psychosis Severe mental illness with serious distortion of thoughts, behaviour, capacity to recognize and of perception such as delusions and hallucinations. Psychosis can broadly categorized in to four groups:

3 Psychosis Acute and Chronic organic brain syndromes (cognitive disorders) such as delirium, dementia, confusion, disorientation, defective memory and disorganized behaviour. Functional disorder: memory and orientation mostly retained by emotion; thought, reasoning and behaviour are altered. Schizophrenia (split mind): splitting of perception and interpretation from reality- hallucinations and inability to think coherently. Described in terms of positive and negative symptoms. Paranoid state: fixed delusions (false beliefs) and loss of insight.

4 Psychosis Environmental factors Maturational factors
Neuronal connectivity Neurotransmitters Receptors/drug targets

5 Environmental Factors
Psychosis Environmental Factors Exposure to infections Toxic/Traumatic/nutritional ( in utero) Insults ALTERATIONS IN NEURODEVELOPMENT Autoimmunity Stress during gestation or early in childhood/adolescence

6 Maturational Processes
Apoptosis Synaptic Pruning Myelination (prenatal to adolescence) Unmasking Genetic Vulnerability

7 Neuronal connectivity
Structural changes during development and in response to environmental factors Changes in neurotransmitter activity in response to environmental factors Neurotrophic factors and changes in gene transcription (eg. neuroregulin-1 which regulates neuronal migration)

8 NEURONAL CONNECTIVITY
Functional activity in neocortex of psychotic patients may be decreased: Myelination Hormonal effects of puberty Exposure to stressors Defective connections in midbrain, thalamus, limbic and prefrontal cortex

9 What is SCHIZOPHRENIA? Schizophrenia is a neurodevelopmental disorder with complex genetics and incompletely understood pathophysiology. Mutations or polymorphisms of many genes appear to contribute to the risk for schizophrenia.

10 STRUCTURAL BRAIN CHANGES IN SCHIZOPHRENIA
Schizophrenics show deficits in tasks involving prefrontal cortex or those requiring working memory Prefrontal cortical thickness is reduced 5-10%, neuron size is down, but no change in neuron number Synaptic connectivity is reduced Medial dorsal thalamus shows 30% reduction in neuron number Prefrontal cortex receives fewer projections from the thalamus

11 STRUCTURAL BRAIN CHANGES IN SCHIZOPHRENIA
Schizophrenia patients have increased mesolimbic DA activity related to positive symptoms. Schizophrenia patients have decreased DA D1 activity in the dorsolateral and ventromedial prefrontal cortex (PFC) that is associated with cognitive deficits and negative symptoms.

12 Schizophrenia - symptoms
Positive Symptoms Hallucinations Delusions Disorganized Thought Perception disturbances Inappropriate emotions Negative Symptoms Blunted emotions Anhedonia Lack of feeling FUNCTION Mood Symptoms Loss of motivation Social withdrawal Insight Demoralization Suicide Cognition New Learning Memory

13 Positive/active symptoms include thought disturbances, delusions, hallucinations
Negative/passive symptoms include social withdrawal, loss of drive, paucity of speech, impaired personal hygiene.

14 Paranoid-type schizophrenia
characterized by delusions and auditory hallucinations but relatively normal intellectual functioning and expression of affect. The delusions can often be about being some other person who is famous. exhibit anger, aloofness, anxiety, and argumentativeness. Delirium: an acutely disturbed state of mind characterized by restlessness, illusions, and incoherence/ A delusion, in everyday language, is a fixed belief that is either false, fanciful, or derived from deception. 14

15 Negative Symptoms - A’s
Affect Flattening Found in about 2/3 of schizophrenic patients Alogia The failure to respond to questions or comments Can also take the form of slow or delayed responses Avolition Inactivity or early loss of interest in ongoing activity Anhedonia -inability to derive pleasure

16 Prevalence of Schizophrenia
1-2% of U.S. population 2 million diagnosed in U.S. Median age at diagnosis = mid-20’s Men = Women prevalence

17 Prognosis of Schizophrenia
10% continuous hospitalization < 30% recovery = symptom-free for 5 years 60% continued problems in living/episodic periods

18 Schizophrenia Pathophysiology
Schizophrenia Pharmacologic Pathophysiology Profile of APDs Past Excess dopaminergic Dopamine D2-receptor activity antagonists Present Renewed interest in the Combined 5-HT2/D2 role of serotonin (5-HT) antagonists Future Imbalance in cortical More selective antagonists communication and Mixed agonist/antagonists cortical-midbrain Neuropeptide analogs integration, involving multiple neurotransmitters

19 DA pathways in the CNS Ref: Goodman and Gilman’s Therapeutic Basis of Pharmacology 19

20 DA-containing pathways in the CNS
There are three major DA-containing pathways in the CNS: The nigrostriatal pathway. The mesocortical pathway, where neurons in the ventral tegmental nucleus project to a variety of midbrain structures and to the frontal cortex . The tuberoinfundibular pathway, which delivers DA to cells in the anterior pituitary 20

21 Dopaminergic Pathways and Innervations

22 Dopaminergic Pathways and Innervations
The mesolimbic pathway is associated with reward and learned behaviors. Dysfunction in this pathway is associated with addiction, schizophrenia, and psychoses (including bipolar depression), and learning deficits. The mesocortical pathway is important for "higher-order" cognitive functions including motivation, reward, emotion, and impulse control. It is also implicated in psychoses, including schizophrenia, and in attention-deficit hyperactivity disorder. The mesolimbic and mesocortical pathways are sometimes grouped together as mesolimbocortical. 22

23 Dopaminergic Pathways and Innervations
The nigrostriatal pathway is a key regulator of movement. Impairments in this pathway are evident in Parkinson disease and underlie detrimental movement side effects associated with dopaminergic therapy, including tardive dyskinesia. DA released in the tuberoinfundibular pathway is carried by the hypophyseal blood supply to the pituitary, where it regulates prolactin secretion 23

24 Schizophrenia What is the present Pathophysiology? 24

25 Schizophrenia What is paranoid type schizophrenia? 25

26 Schizophrenia Paranoid type is characterized by organized system of delusions and auditory hallucination. Individual is often tense, suspicious, and guarded. 26

27 Schizophrenia: A case study
Tony, age 21, has been diagnosed with paranoid schizophrenia. He has been socially isolated and hearing voices telling him to kill his parents. He has been admitted to the psychiatric unit from the ED. What would be the INITIAL intervention for Tony? 27

28 Schizophrenia: A case study
Ensure a safe environment for him and others Decrease his anxiety and increase trust Antipsychotic drugs to decrease psychotic symptoms 28

29 Dopamine recognized as a neurotransmitter in the 1950’s
DOPAMINE RECEPTORS Dopamine recognized as a neurotransmitter in the 1950’s Five dopamine receptor subtypes: D-1,-2,-3,-4,-5 Schizophrenics show elevated D2 receptor number Cortex has much higher amounts of D1 than D2 receptors chronic antipsychotic drugs downregulate D1’s in the cortex and striatum

30 Schizophrenia - Dopamine Hypothesis
Repeated administration of stimulants like amphetamines and cocaine cause a psychosis - resembles the positive symptoms of schizophrenia Stress can produce a psychotic state in recovered amphetamine addicts. Carlsson and Lindqvist (1963) first proposed that drugs such as chlorpromazine and haloperidol alleviate schizophrenic symptoms by blocking DA receptors. These antipsychotic medications have in common their ability to block dopamine D2 receptors

31 Schizophrenia - Dopamine Hypothesis
A strong correlation between the affinity of antipsychotic drugs for DA receptors and their clinical potency But no clear and consistent abnormality in DA function has been detected in schizophrenic patients. Some early studies with postmortem tissue revealed increased numbers of DA receptors (in particular D2-like) in schizophrenic patients. Reduced cortical dopamine transmission induced by long-term phencyclidine (PCP) exposure may be associated with a hyperactivity of subcortical dopamine systems

32

33 Schizophrenia - Serotonin Hypothesis
correlation between DA affinity and antipsychotic efficacy has become weaker as a result of recently developed atypical antipsychotic medications that also show substantial affinity for 5HT2 receptors. Alteration of 5-HT transmission in the brains of schizophrenics patients have been reported in post-mortem studies and serotonin-agonists challenge studies. There are widespread and complex changes in the 5-HT system in schizophrenics patients. These changes suggest that 5-HT dysfunction is involved in the pathophysiology of the disease.

34 Serotonin-Dopamine Interactions Ventral Tegmental Area
Prefrontal Cortex Dopamine (DA) Serotonin (5-HT) GABA Glutamate Striatum GABA/ACh Motor Outputs Limbic System Blockade of D2 receptors by conventional APDs causes EPS Ventral Tegmental Area Substantia Nigra 5-HT2A antagonists release dopamine from inhibition and decrease EPS Median Raphe Dorsal Raphe

35 Schizophrenia - Glutamate Hypothesis
Cognitive dysfunction is the greatest predictor of poor functional outcome in schizophrenia and shows limited response to antipsychotic treatment. Glutamate NMDA receptor stimulation is involved in tonic inhibition of mesolimbic DA release, but facilitates mesocortical DA release. The NMDA antagonists phencyclidine and ketamine indirectly act to stimulate DA availability by decreasing the glutamate-mediated tonic inhibition of DA release in the mesolimbic DA pathway.

36 Schizophrenia Schizophrenia has at least _____ symptoms, each present for a significant portion of the time during a _________ period and continuous signs of disturbance for at least _________.

37 Schizophrenia About half the people with schizophrenia display significant difficulties with __________ and other kinds of cognitive functioning.

38 Schizophrenia What is the medical term for “Poverty of speech”?

39 General Goals of Pharmacotherapy
The immediate goal of antipsychotic treatment is to decrease in acute symptoms that induce patient distress, particularly behavioral symptoms (e.g., hostility, agitation). The dosing, route of administration, and choice of antipsychotic depend on the underlying disease state, clinical acuity, drug-drug interactions with concomitant medications, and patient sensitivity to short- or long-term adverse effects. - that may present a danger to the patient or others

40 General Goals of Pharmacotherapy
With the exception of clozapine's superior efficacy in treatment-refractory schizophrenia, neither the clinical presentation nor biomarkers predict the likelihood of response to a specific antipsychotic class or agent. As a result, avoidance of adverse effects based upon patient and drug characteristics, are the principal determinants for choosing initial antipsychotic therapy. - that may present a danger to the patient or others

41 General Goals of Schizophrenia
The immediate goals of acute antipsychotic treatment are: reduction of agitated, disorganized, or hostile behavior decreasing the impact of hallucinations, improvement of organization of thought processes, reduction of social withdrawal. - that may present a danger to the patient or others

42 General Goals of Schizophrenia
Doses used are often higher than those required for maintenance treatment of stable patients. Despite considerable debate, newer atypical antipsychotic agents are not more effective in the treatment of positive symptoms than typical agents although there may be small but measurable differences in effects on negative symptoms and cognition. - that may present a danger to the patient or others

43 Refractory Schizophrenia
Refractory schizophrenia is defined using the Kane criteria: failed 6-week trials of two separate agents and a third trial of a high-dose typical antipsychotic agent (e.g., haloperidol or fluphenazine 20 mg/day). In this patient population, response rates to typical antipsychotic agents, defined as 20% symptom reduction using standard rating scales (e.g., Positive and Negative Syndrome Scale [PANSS]. - Lack of response to adequate antipsychotic drug doses for adequate periods of time may indicate treatment-refractory illness.

44 Significance of antipsychotics/neuroleptics
Introduction of chlorpromazine in 1952 led by the end of the 1950’s to emptying psychiatric hospitals back into community, with mixed results. The successful treatment of a psychiatric disorder with a drug led to a search for biological mechanisms.

45 ANTIPSYCHOTICS Pre-90’s Post-90’s
“Typical”, conventional, traditional neuroleptics, major tranquilizors Modeled on D2 antagonism EPS/TD Post-90’s “Atypical”, novel, 2nd generation Modeled on 5-HT2/D2 antagonism Less EPS, prolactin effects Weight gain, sedation, diabetes

46 Antipsychotic drugs Antipsychotic drugs are also known as neuroleptics, ataractic, major tranquilizer and anti-schizophrenic drugs. A first generation antipsychotic known as typical antipsychotic was discovered in 1950s. Most of the drugs are in the second generation, known as atypical antipsychotics, have been developed more recently. 46

47 Antipsychotics: site of action

48 Classification Typical antipsychotics Phenothiazines:
a. aliphatic side chains: Chlorpromazine, Triflupromazine. b. Piperidine side chain: Thioridazine c. Piperazine side chain: Trifluoperazine, fluphenazine. 2. Butyrophenones: Haloperidol, Trifluperidol. 3. Thioxanthenes: Chlorprothixene, Flupenthixole

49 Classification of antipsychotic drugs
Atypical antipsychotic lower affinity for D2 receptors than typical antipsychotic drugs and high 5-HT2 antagonist effects. Olanzipine Clozapine Sertindole Risperidone

50 Goal of antipsychotic treatment
The immediate goal of antipsychotic treatment: Decrease in acute symptoms that induce patient distress- e.g. behavioral symptoms that present a danger to the patient or others. The dosing, route of administration, and choice of antipsychotic depend on the underlying disease state, drug-drug interactions with concomitant medications, and patient sensitivity to short- or long-term adverse effects. Neither the clinical presentation nor biomarkers predict the likelihood of response to a specific antipsychotic class or agent. Avoidance of adverse effects based upon patient and drug characteristics, or exploitation of certain medication properties are the principal determinants for antipsychotic therapy. (e.g., hostility, agitation). With the exception of clozapine's superior efficacy in treatment-refractory schizophrenia

51 MECHANISMS OF ACTION OF TYPICAL NEUROLEPTICS
DOPAMINE-2 receptor blockade in meso-limbic and meso-cortical systems for antipsychotic effect. DOPAMINE-2 receptor blockade in basal ganglia (nigro-striatal system) for EPS. DOPAMINE-2 receptor supersensitivity in nigrostriatal system for tardive dyskinesia

52 LONG TERM EFFECTS OF D2 RECEPTOR BLOCKADE:
Dopamine neurons reduce activity. Postsynaptic D-2 receptor numbers increase (compensatory response). When D2 blockade is reduced, DA neurons resume firing and stimulate increased number of receptors >> hyper-dopamine state >> tardive dyskinesia

53 MANAGEMENT OF EPS Dystonia and parkinsonism: anticholinergic antiparkinson drugs Neuroleptic malignant syndrome: muscle relaxants, DA agonists, supportive Akathisia: benzodiazepines, propranolol Tardive dyskinesia: increase neuroleptic dose; switch to clozapine

54 Typical Antipsychotics: adverse Effects
Sedation ‑ initially considerable; tolerance usually develops after a few weeks of therapy. Postural hypotension ‑ results primarily from adrenergic blockade; tolerance can develop. Anticholinergic effects ‑ include blurred vision, dry mouth, constipation, urinary retention; results from muscarinic cholinergic blockade. Endocrine effects ‑ increased prolactin secretion can cause galactorhea; results from antidopamine effect Hypersensitivity reactions ‑ jaundice, photosensitivity, rashes, agranulocytosis can occur. Idiosyncratic reactions ‑ malignant neuroleptic syndrome (MNS). Weight gain Neurological side effects H1 blockade.

55 Antipsychotic Medications
Conventional medications (Typical/ older): haloperidol (Haldol) fluphenazine (Prolixin) pimozide (Orap) trifluoperazine (Stelazine) thiothixene (Navane) perphenazine (Trilafon) mesoridazine (Serentil) loxapine (Loxitane) molindone (Moban) thioridazine (Mellaril) chlorpromazine (Thorazine)

56 Antipsychotic Medications
Atypical medications (newer): clozapine (Clozaril) risperidone (Resperidal) olanzapine (Zyprexa) quetiapine (Seroquel) ziprasodone (Geodon) aripiprazole (Abilify) paliperidone (Invega) iloperidone (Fanapt) asenapine (Saphris) lurasidone (Latuda)

57 Neurological Side Effects of antipsychotics
REACTION FEATURES TIME OF MAXIMAL RISK PROPOSED MECHANISM TREATMENT Acute dystonia Spasm of muscles of tongue, face, neck, back; may mimic seizures; not hysteria 1 to 5 days Unknown Antiparkinsonian agents are diagnostic and curative Akathisia Motor restlessness; not anxiety or "agitation" 5 to 60 days Reduce dose or change drug: antiparkinsonian agents,b benzodiazepines or propranololc may help Parkinsonism Bradykinesia, rigidity, variable tremor, mask facies, shuffling gait 5 to 30 days Antagonism of dopamine Antiparkinsonian agents helpful Neuroleptic malignant syndrome Catatonia, stupor, fever, unstable blood pressure, myoglobinemia; can be fatal Weeks; can persist for days after stopping neuroleptic Antagonism of dopamine may contribute Stop neuroleptic immediately: dantrolene or bromocriptined may help: antiparkinsonian agents not effective Perioral tremor ("rabbit" syndrome) Perioral tremor (may be a late variant of parkinsonism) After months or years of treatment Antiparkinsonian agents often help Tardive dyskinesia Oral-facial dyskinesia; widespread choreoathetosis or dystonia After months or years of treatment (worse on withdrawal) Excess function of dopamine hypothesized Prevention crucial; treatment unsatisfactory a. Many drugs have been claimed to be helpful for acute dystonia. Among the most commonly employed treatments are diphenhydramine hydrochloride, 25 or 50 mg intramuscularly, or benztropine mesylate, 1 or 2 mg intramuscularly or slowly intravenously, followed by oral medication with the same agent for a period of days to perhaps several weeks thereafter. b. For details regarding the use of oral antiparkinsonian agents, see the rest of slides c. Propranolol often is effective in relatively low doses (20-80 mg per day). Selective beta1-adrenergic receptor antagonists are less effective. d. Despite the response to dantrolene, there is no evidence of an abnormality of Ca2+ transport in skeletal muscle; with lingering neuroleptic effects, bromocriptine may be tolerated in large doses (10-40 mg per day).

58 Adverse Effects - EPS Parkinson-like symptoms Tardive dyskinesia
Details on two main extrapyramidal disturbances (EPS): Parkinson-like symptoms tremor, rigidity direct consequence of block of nigrostriatal DA2 R reversible upon cessation of antipsychotics Parkinsonism resembling its idiopathic form occurs when striatal D2 occupancy exceeds 78%, and often responds to dose reduction or switching to an antipsychotic with weaker D2 antagonism Tardive dyskinesia involuntary movement of face and limbs less likely with atypical antipsychotics (AP) appears months or years after start of AP result of proliferation of DA R in striatum treatment is generally unsuccessful

59 Antipsychotic Medications (Neuroleptics)
Uses: -reduce hallucinations -improve organization of thought processes -reduce preoccupations with improbable beliefs -tranquilization -anti-emesis

60 Common Side effects of antipsychotics:
sedation drowsiness anergy decreased motivation slowing of thought processes depression dry mouth constipation blurred vision weight gain, diabetes, hyperlipidemia orthostatic hypotension amenorrhea galactorrhea gynecomastia

61 Common Side effects of antipsychotics:
rashes sun sensitivity sexual dysfunction restlessness restless leg syndrome headache (especially aripiprazole and ziprasidone) nausea and vomiting (especially risperidone and ziprasidone)

62 Neurological side effects of antipsychotics
Parkinsonian Side Effects Onset generally about 7 days after beginning antipsychotic medications Key features: "pill-rolling" tremor increased muscle tone stooped, shuffling gait bradykinesia impaired balance

63 Neurological side effects of antipsychotics
Akathisia Characterized by extreme motor restlessness or "nervousness" People may be observed to pace, jog their legs, repeatedly sit then stand When severe, people may not be able to sleep May be a cause of increased aggression in people having developmental disabilities Onset: immediate to a few days

64 Neurological side effects of antipsychotics
Dystonia Characterized by a sustained, painful contraction of one or more muscle groups. Common presentations: rigid tongue protrusion throat "closing up" or tongue drawn back upward deviation of the eyes Onset: frequently within an hour of dosage, may be recurrent Can be lethal if airway obstruction occurs

65 Neurological side effects of antipsychotics
Tardive Dyskinesia Characterized by involuntary muscle movements Onset generally after many years of taking antipsychotic medications, but can occur within weeks Can be progressive and permanent Typical movements: chewing, lip-smacking, lip-licking, puffing frequent blinking tongue flickering or protrusion foot tapping, ankle movements shrugging, twisting of torso, reflux, vomiting Progresses to cause respiratory difficulties, aspiration pneumonia

66 Serious side effects of antipsychotics
neutropenia seizures neuroleptic malignant syndrome cardiac arrhythmias hyperthermia cataracts precipitation of glaucoma diabetes hyperlipidemia

67 Phenothiazines - Side effects
Weight gain – 40% - weight gain now attributed to ratio of binding to D2 and 5-HT2 receptors; also histamine. Sexual dysfunction result from NE blockade erectile dysfunction in 23-54% of men loss of libido in men and women Seizures - <1% for generalized grand mal

68 Phenothiazines - Side effects
Neuroleptic malignant syndrome (1-2% early in trt) combination of motor rigidity, hyperthermia, and autonomic dysregulation of blood pressure and heart rate (both go up) can be fatal in 5-20% of cases if untreated treatment – discontinue medicines; treatments for fever and cardiac problems.

69 some phenothiazines collect in skin (chlorpromazine)
Sensitivity to sun some phenothiazines collect in skin (chlorpromazine) sunlight causes pigmentation changes – grayish-purple spot. can also occur in eye and cause brown in cornea Agranulocytosis - <1% reduced white blood cell count lowered resistance to infection can be fatal Jaundice – elevated bilirubin in liver - < ½% this produces a brownish cloud to vision and possibly permanent impairment

70 Phenothiazines – Metabolism and Drug Interactions
Metabolized by CYP2D6. Over 10 identified human metabolites, most inactive. Enzyme interactions with 3A4 inducers barbiturates (phenobarbital); phenytoin (Dilantin); carbamazepine (Tegretol) – reduce phenothiazine levels co-administration must be carefully monitored to prevent toxicity enzyme competition with SSRIs increases levels and may increase side effects

71 Haloperidole entered US market in 1967
more potent than phenothiazines, so doses are lower also have long half-life like phenothiazines, they block dopamine and norepinephrine receptors and show the related side effects extrapyramidal effects are worse but blood pressure effects are less reduced sedation no blood abnormalities or jaundice

72 Haloperidole: Metabolism
Multiple CYP pathways, particularly 2D6, 3A4, and minor pathway 1A2. One active metabolite, reduced haloperidol (formed by ketone reductase). Reduced haloperidol inhibits CYP2D6 and may be re-oxidized to the parent drug. Therapeutic serum levels not well defined; 5-20 ng/mL used as a target for dosing.

73 Limitations Of Conventional Antipsychotics
Approximately one-third of patients with schizophrenia fail to respond Limited efficacy against Negative symptoms Affective symptoms Cognitive deficits High proportion of patients relapse Side effects and compliance issues Some safety issues are prominent

74 Antipsychotic Drugs – New Generations “atypical”
About 40-60% do not respond to phenothiazines or cannot handle side effects Questions remain about the efficacy of phenothiazines and haloperidole for negative symptoms Drugs needed that are low in extrapyramidal side effects and at least equal in efficacy for positive symptoms, perhaps better for negative

75 Antipsychotic Drugs – New Generations “atypical”
clozapine risperidone olanzapine sertindole quetiapine etc.

76 Atypical antipsychotics
MARTA (multi acting receptor targeted agents) clozapine, olanzapine, quetiapine SDA (serotonin-dopamine antagonists) risperidone, ziprasidone, sertindole Selective D2/D3 antagonists sulpiride, amisulpiride

77 Clozapine (1989) Selectively blocks dopamine D2 receptors, avoiding nigrostriatal pathway Also blocks NE More strongly blocks 5-HT2 receptors in cortex which then acts to modulate some dopamine activity Among non-responders to first generation meds or those who cannot tolerate side effects, about 30% do respond to Clozapine

78 Clozapine Extrapyramidal side effects are minimal
May help treat tarditive dyskinesia shows orthostatic hypotension effects, sedation, weight gain, increased heart rate Increased risk for seizures (2-3%) Agranulocytosis in 1% Agranulocytosis risks increase when co-administered with carbamazepine Interactions with SSRIs and valproic acid increase Clozapine levels and risks

79 Risperidone (1994) Fewer side effects than Clozapine
Marketed as first line approach to treatment Blocks selective D2 and 5-HT2 Argued as effective for positive and negative symptoms (controversial) Extrapyramidal side effects low (but are shown at high doses) - controversial Shares sedation, weight gain, rapid heart beat, orthostatic hypotension, and elevated prolactin No agranulocytosis risks May cause anxiety/agitation (possible OCD)

80 Risperidone (Risperdal)
Research designs clearly stacked in favor of Risperidone showing better profile for extrapyramidal side effects and for symptom reduction Advantages unclear other than agranulocytosis issue

81 Olanzipine - Zyprexa – 1996 Same poorly supported arguments about improved negative symptom reduction Argued to be better than risperidone in extrapyramidal issues Does not cause prolactin elevation Same claim to fame reduced agranulocytosis risks

82 Sertindole – Serlect – 1995 Some poorly supported arguments about improved negative symptom reduction Low risk for extrapyramidal side effects – major advantage No sedation and very mild prolactin elevation– major advantages Shares orthostatic hypotension, tachycardia, and weight gain Common side effects are rhinitis and reduced ejaculatory volume (not associated with disturbed function) concern about sudden cardiac death or episodes due to cardiac arrhythmia led to its voluntary removal in 1998

83 Quetiapine – Seroquel - 1997
No increased risks for extrapyramidal symptoms Shares sedation, orthostatic hypotension, weight gain Does cause anticholinergic side effects (like older and Clozapine) – dry mouth, constipation Does not elevate prolactin Ziprasidone Similar to advantages of others, but argued not to cause weight gain

84 Status Limited evidence to support arguments about improved treatment of negative symptoms clearly do have reduced extrapyramidal side effects, reduced sedation, and do not cause prolactin elevation Weight gain issue – is ziprasidone better? Wetterling Evaluation of published data from varying designs, etc: Clozapine – 1.7 kg/month Risperidone – 1 kg/month Olanzipine – 2.3 kg/month Ziprasidone – 0.8 kg/month Quetiapine kg/month

85 Pharmacological effects
Effects on dopamine systems i. Mesolimbic/ mesocortical ii. Nigrostriatal iii. Tuberoinfundibular Dopamine receptors and their effects i. D1/D5 ii. D2/D3/D4 family

86 Dopamine partial agonist
no clinically available effective antipsychotic is devoid of D2 antagonistic activity. This reduction in dopaminergic neurotransmission is presently achieved through one of two mechanisms: D2 antagonism or partial D2 agonism, Of which aripiprazole is the only current example. Emerging data indicate that stimulation of glutamate or muscarinic receptors confer antipsychotic properties

87 Antipsychotics Aripiprazole has an affinity for D2 receptors intrinsic activity is ~25% that of dopamine. In the absence of DA, aripiprazole produces a maximal level of D2 activity ~25% that of DA. The potent D2 antagonist haloperidol is capable of reducing dopamine's effect to zero, but when DA is incubated with increasing concentrations of aripiprazole, maximal inhibition of D2 activity did not exceed 25% of the DA response, that is, the level of agonism provided by aripiprazole.

88 Aripiprazole (mechanism of action)

89 Antipsychotics Aripiprazole's capacity to stimulate D2 receptors in brain areas where synaptic DA levels are limited (e.g., PFC neurons) or decrease dopaminergic activity when dopamine concentrations are high (e.g., mesolimbic cortex) is thought to be the basis for its clinical effects in schizophrenia.FDA approval. The potent D2 antagonist haloperidol is capable of reducing dopamine's effect to zero, but when DA is incubated with increasing concentrations of aripiprazole, maximal inhibition of D2 activity did not exceed 25% of the DA response, that is, the level of agonism provided by aripiprazole.

90 Metabolism 2D6 and 3A4 convert aripiprazole to active metabolite dehydro-aripiprazole. Metabolite has longer t1/2 (75 vs. 94 hours).

91 CLOZAPINE: AN EXAMPLE OF AN ATYPICAL NEUROLEPTIC
Clozapine (sold as Clozaril, Leponex, Fazaclo; Gen-Clozapine in Canada) was the first of the atypical antipsychotics to be developed. It was approved by the United States Food and Drug Administration (FDA) in 1989 and is the only FDA-approved medication indicated for treatment-resistant schizophrenia and for reducing the risk of suicidal behaviour in patients with schizophrenia. [dubious – discuss] Clozapine has been shown to be superior in efficacy in treating schizophrenia. Were it not for its side effects it would be first line treatment; however the rare but potentially lethal side effects of agranulocytosis and myocarditis relegate it to third-line use. Furthermore it may rarely lower seizure threshold, cause hepatic dysfunction, weight gain and be associated with type II diabetes. More common side effects are predominantly anticholinergic in nature, with dry mouth, sedation and constipation. It is also a strong antagonist at different subtypes of adrenergic, cholinergic, histaminergic and serotonergic receptors. Safer use of clozapine requires weekly blood monitoring for around five months followed by four weekly testing thereafter. Echocardiograms are recommended every 6 months to exclude cardiac damage.

92 . There is now ample evidence to suggest that neuroleptics (aka. anti-psychotics and major tranquillizers) are dangerous drugs, and patients’ exposure to them should be minimized wherever possible. This clinical imperative applies whether neuroleptics are of the traditional type or atypical variety, albeit for different reasons since the traditional agents are neurotoxic while atypicals are mainly metabolic poisons. Usage of traditional neuroleptics seems indeed to be declining progressively, but the opposite seems to be happening for ‘atypicals’, and new indications for these drugs are being promoted. Yet the atypical neuroleptics are a category of pharmaceuticals which are close to being un-necessary since there are safer, cheaper and pleasanter substitutes such as benzodiazepines and the sedative antihistamines (eg. promethazine). “In terms of therapeutic value, it therefore seems likely that 'atypicals' are merely an unusually dangerous way of sedating patients. In therapeutic terms these drugs therefore represent a significant backward step. Rationally, the atypicals should now be dropped and replaced with safer sedatives. Potential neuroleptic-substitutes which already exist would include benzodiazepines and sedative antihistamines such as promethazine [4,8].”

93 Atypicals have less tendency to produce motor side effects
Clozapine is generally referred to as an "atypical" neuroleptic. What is the difference between "atypical" and "typical" neuroleptics (such as haloperidol)? There is no rigorous line between typical and atypical neuroleptics…but Atypicals have less tendency to produce motor side effects Atypicals produce effects on negative symptoms of schizophrenia May have effects in therapy-resistant patients

94 Parkinson's disease Parkinson's disease (PD also known as idiopathic or primary parkinsonism) is a degenerative disorder of the central nervous system. The motor symptoms of Parkinson's disease result from the death of dopamine-generating cells in the substantia nigra, a region of the midbrain; the cause of this cell death is unknown. Early in the course of the disease, the most obvious symptoms are movement-related; these include shaking, rigidity, slowness of movement and difficulty with walking and gait. Later, thinking and behavioral problems may arise, with dementia commonly occurring in the advanced stages of the disease, whereas depression is the most common psychiatric symptom. Other symptoms include sensory, sleep and emotional problems. Parkinson's disease is more common in the elderly, with most cases occurring after the age of 50

95 Parkinson's disease The four primary symptoms of PD are tremor, or trembling in hands, arms, legs, jaw, and face; rigidity, or stiffness of the limbs and trunk; bradykinesia, or slowness of movement; and postural instability, or impaired balance and coordination. As these symptoms become more pronounced, patients may have difficulty walking, talking, or completing other simple tasks. PD usually affects people over the age of 50.  Early symptoms of PD are subtle and occur gradually. 

96 Clinical features of PD
Three cardinal symptoms: ® resting tremor ® bradykinesia (generalized slowness of movements) ® muscle rigidity Clinically, PD is characterized by three cardinal symptoms: resting tremor, bradykinesia (generalized slowness of movements) and muscle rigidity.

97 Clinical features of PD
Resting tremor: Most common first symptom, usually asymmetric and most evident in one hand with the arm at rest. Bradykinesia: Difficulty with daily activities such as writing, shaving, using a knife and fork, and opening buttons; decreased blinking, masked facies, slowed chewing and swallowing. Rigidity: Muscle tone increased in both flexor and extensor muscles providing a constant resistance to passive movements of the joints; stooped posture, anteroflexed head, and flexed knees and elbows. The most common first symptom is resting tremor, which is usually asymmetric and most evident in one hand with the arm at rest. It is the most easily recognized sign of the disease. The frequency of parkinsonian tremor is low, typically in the 3-6 Hz range. The alternating contraction of agonist and antagonist muscles of the forearm results in a "pill-rolling" tremor. Bradykinesia is the central motor abnormality in PD. Difficulties with daily activities such as writing, shaving, cutting food with a knife and fork and opening or buttoning buttons, as well as decreased blinking, masked facies, slowed chewing and swallowing and drooling reflect bradykinesia. Muscle tone is increased in both flexor and extensor muscles providing a constant resistance to passive movements of the joints (a "cog-wheel" rigidity can be felt during passive movements of joints). Rigidity underlies the chracteristic stooped posture, anteroflexed head, and flexed knees and elbows in the patients. The symptoms typically start asymmetrically from one side spreading from one affected limb on one side to the other limb on the same side (e.g. from hand to leg), and later also to contralateral side. Koller, WC and Minagan, A. Treatment strategies for the management of Parkinson’s disease. In: Parkinson’s disease management guide, Medical economics Company Inc. at Montvale NJ, pp , 2001

98 Additional clinical features of PD
Postural instability: Due to loss of postural reflexes. Dysfunction of the autonomic nervous system: Impaired gastrointestinal motility, bladder dysfunction, sialorrhea, excessive head and neck sweating, and orthostatic hypotension. Depression: Mild to moderate depression in 50 % of patients. Cognitive impairment: Mild cognitive decline including impaired visual-spatial perception and attention, slowness in execution of motor tasks, and impaired concentration in most patients; at least 1/3 become demented during the course of the disease. In addition to these three cardinal features, postural instability, dysfunction of the autonomic nervous system, depression and cognitive impairment are common. Loss of postural reflexes causes balance difficulties and the body can move or fall into the direction of the center of gravity. Therefore, turning or bending forward may be associated with involuntary steps. Autonomic dysfunction can result into impaired gastrointestinal motility causing sense of fulness and constipation. Furthermore, bladder dysfunction (urinary frequency, urgency and urge incontinence), sialorrhea (due to excessive saliva production and decreased frequency of swallowing), excessive head and neck sweating (resulting from altered thermoregulation), and orthostatic hypotension result from autonomic dysfunction. Approximately 50 % of patients show mild to moderate depression. Many patients show mild cognitive decline including impaired visual-spatial perception and attention, slowness in execution of motor tasks and impaired concentration. At least 1/3 of the patients become demented during the course of the disease. Koller, WC and Minagan, A. Treatment strategies for the management of Parkinson’s disease. In: Parkinson’s disease management guide, Medical economics Company Inc. at Montvale NJ, pp , 2001

99 Functional neuroanatomy of PD
Substantia nigra: The major origin of the dopaminergic innervation of the striatum. Part of extrapyramidal system which processes information coming from the cortex to the striatum, returning it back to the cortex through the thalamus. One major function of the striatum is the regulation of posture and muscle tonus. Substantia nigra is the major origin of the dopaminergic innervation of the striatum and is part of so called extrapyramidal system which processes information coming from the cortex to the striatum, and returns it back to the cortex through the thalamus. One major function of the striatum, which is under the control of substantia nigra, is the regulation of posture and muscle tonus. Source: Marsden, C. D. Parkinson's disease. Lancet 335, , 1990

100 Dopamine pathways in human brain
The ventral tegmental area (VTA) cells project to limbic (mesolimbic projection) and cortical (mesocortical projection) areas. Neurons of the substantia nigra project to the striatum (nigrostriatal projection). In PD, dopaminergic nerve cells in the substantia nigra develop nerve cell loss, and its degeneration and the resulting striatal dopamine depletion are responsible for most of the motor abnormalities.

101 Neurochemistry of PD PD symptoms become manifest when about % of the DA-containing neurons in the substantia nigra and % of striatal DA are lost. The ventral tegmental area (VTA) cells project to limbic (mesolimbic projection) and cortical (mesocortical projection) areas. Neurons of the substantia nigra project to the striatum (nigrostriatal projection). In PD, dopaminergic nerve cells in the substantia nigra develop nerve cell loss, and its degeneration and the resulting striatal dopamine depletion are responsible for most of the motor abnormalities In late 1950s, it was shown that dopamine is present in mammalian brain, and that the levels are highest within the striatum. In 1960, Ehringer and Hornykiewicz showed that the levels of dopamine are severely reduced in the striatum of patients with PD. Degeneration of the nigrostriatal dopaminergic neurons causes symptoms of PD: symptoms become manifest when about % of the dopamine-containing neurons in the substantia nigra and % of striatal dopamine are lost. Carlsson, A. The occurrence, distribution and physiological role of catecholamines in the nervous system. Pharmacol. Rev. 11, , 1959 Sano, I. et al. Distribution of catechol compounds in human brain. Biochim. Biophys. Acta 32, , 1959 Ehringer, H. & Hornykiewicz, O. Verteilung von Noradrenalin und Dopamin (3-Hydroxytyramin) im Gehirn des Menschen und ihr Verhalten bei Ekrankungen des extrapyramidalen Systems. Klin. Wschr. 38, (1960) Marsden, C. D. Parkinson's disease. Lancet 335, , 1990 Forno, L. S. Neuropathology of Parkinson's disease. J. Neuropathol. Exp. Neurol. 55, , 1996 Koller, WC and Minagan, A. Treatment strategies for the management of Parkinson’s disease. In: Parkinson’s disease management guide, Medical economics Company Inc. at Montvale NJ, pp , 2001.

102 Dopamine synthesis Dopamine is synthesized from tyrosine, which is first catalysed to L-DOPA by tyrosine hyroxylase. L-DOPA is then decarboxylated to dopamine by dopadecarboxylase, and stored in the vesicles. When released into synaptic cleft, dopamine binds to receptors (D1-D5 in the figure), which activates different second messenger systems inside the cell causing changes in excitability, metabolism and gene expression. Reuptake of dopamine is by dopamine transporter. If unstored in the cytosol, dopamine is oxidized by monoamine oxidase (MAO).

103 Therapy of PD: levodopa
Late 1950s: L-dihydroxyphenylalanine (L-DOPA; levodopa), a precursor of DA that crosses the blood-brain barrier, could restore brain DA levels and motor functions in animals treated with catecholamine depleting drug (reserpine). First treatment attempts in PD patients with levodopa resulted in dramatic but short-term improvements; took years before it become an established and succesfull treatment. Still today, levodopa cornerstone of PD treatment; virtually all the patients benefit. In late 1950´s, it was shown that L-dihydroxyphenylalanine (L-DOPA; levodopa), a precursor of dopamine that crosses the blood-brain-barrier, could restore brain dopamine levels and motor functions in animals treated with catecholamine depleting drug, reserpine. The observations about the striatal dopamine depletion in PD were followed by attempts to alleviate the symptoms through the administration of levodopa. First attempts resulted in dramatic but short-term improvements. It took years before this treatment become an established and succesfull treatment for PD. Still today, it continues to be the cornerstone of PD treatment. Virtually all PD patients benefit from levopoda treatment. Cotzias, G. C. et al. Modification of parkinsonism: chronic treatment with L-DOPA. N. Engl. J. Med. 280, , 1969. Koller, WC and Minagan, A. Treatment strategies for the management of Parkinson’s disease. In: Parkinson’s disease management guide, Medical economics Company Inc. at Montvale NJ, pp

104 Therapy of PD: limitations of levodopa
Efficacy tends to decrease as the disease progresses. Chronic treatment associated with adverse events (motor fluctuations, dyskinesias and neuropsychiatric problems). Levodopa therapy has, however, its limitations. The efficacy of the therapy is greatest during the early stages of the disease, and tends to decrease as the disease progresses. Chronic levodopa treatment is also associated with the development of adverse events (motor fluctuations, dyskinesias and neuropsychiatric problems) in the majority of patients.

105 Inhibition of peripheral COMT by entacapone increases the amount of L-DOPA and dopamine in the brain and improves the alleviation of PD symptoms. Catechol-O-methyl-transferase (COMT) inhibitors, like entacapone, which increase the bioavailability of levodopa by inhibiting COMT enzyme peripherally and thus slow down the breakdown of levodopa, can be used as adjunctive therapy to levodopa to reduce some of the adverse effects related to long-term levodopa treatment (results in smoother levodopa plasma levels, and a decrease in motor fluctuations in patients).

106 Therapy of PD: limitations of levodopa
Does not prevent the continuous degeneration of nerve cells in the subtantia nigra, the treatment being therefore symptomatic. Levodopa does not however prevent the continuing degeneration of nerve cells in the substantia nigra, the treatment being therefore symptomatic. Koller, WC and Minagan, A. Treatment strategies for the management of Parkinson’s disease. In: Parkinson’s disease management guide, Medical economics Company Inc. at Montvale NJ, pp

107 Therapy of PD: Other treatments
DA receptor agonists (bromocriptine, pergolide, pramipexole, ropinirole, cabergoline) Amantadine Anticholinergics In addition to levopoda, other drugs increasing dopaminergic activity can be used as symptomatic treatments. These include e.g. dopamine receptor agonists (e.g. bromocriptine, pergolide, pramipexole, ropinirole, cabergoline) which directly stimulate striatal dopamine receptors, and are thus independent of the degenerating dopaminergic projections of the substantia nigra for their mechanism of action. Amantadine is an antiviral agent which also increases dopamine release, blocks dopamine reuptake, and stimulates dopamine receptors. It is also a non-competitive NMDA receptors antagonist. However its mechanism of action at therapeutic doses in PD is still under discussion. Normally there is a balance between dopaminergic and cholinergic neurotransmission in the striatum, which is disrupted in PD due to dopamine depletion resulting in a state of relative cholinergic sensitivity, so that cholinergic drugs exacerbate and anticholinergic drugs improve parkinsonian symptoms. Anticholinergics can be used in younger PD patients and are useful for treating resting tremor, but adverse effects (such as memory impairments, acute confusion and hallucinations, as well as peripheral side effects) are common are limit their use. Koller, WC and Minagan, A. Treatment strategies for the management of Parkinson’s disease. In: Parkinson’s disease management guide, Medical economics Company Inc. at Montvale NJ, pp

108 What is Alzheimer’s ? Alzheimer's disease (AD), also known as Senile Dementia of the Alzheimer Type (SDAT) or simply Alzheimer’s is the most common form of dementia. This incurable, degenerative, terminal disease was first described by a German psychiatrist and neuropathologist Alois Alzheimer in 1906 and was named after him. Alzheimer's disease (AD) is a slowly progressive disease of the brain that is characterized by impairment of memory and eventually by disturbances in reasoning, planning, language, and perception. Many scientists believe that Alzheimer's disease results from an increase in the production or accumulation of a specific protein (beta-amyloid protein) in the brain that leads to nerve cell death.

109 Generally, it is diagnosed in people over 65 years of age, although the less-prevalent early onset of Alzheimer’s can occur much earlier. In 2006, there were 26.6 million sufferers worldwide. Alzheimer’s is predicted to affect 1 in 85 people globally by 2050. Alzheimer’s disease

110 Stages of Alzheimer’s Disease

111 Symptoms of Developing A.D
1) Early Stage This is considered as a mild/early stage and the duration period is 2-4 years. Frequent recent memory loss, particularly of recent conversations and events. Repeated questions, some problems expressing and understanding language. Writing and using objects become difficult and depression and apathy can occur. Need reminders for daily activities and difficulties with sequencing impact driving early in this stage.

112 Continued 2) Second stage
This is considered as a middle/moderate stage and the duration is 2-10 years.  Pervasive and persistent memory loss impacts life across settings. Rambling speech, unusual reasoning, confusion about current events, time, and place.  Slowness, rigidity, tremors, and gait problems impact mobility and coordination.  Need structure, reminders, and assistance with activities of daily living.

113 Continued Increased memory loss and confusion.
3) Moderate stage Increased memory loss and confusion. Problems recognizing family and friends. Inability to learn new things. Difficulty carrying out tasks that involve multiple steps (such as getting dressed). Problems coping with new situations. Delusions and paranoia. Impulsive behavior. In moderate AD, damage occurs in areas of the brain that control language, reasoning, sensory processing, and conscious thought

114 Continued 4) Last stage This is considered as the severe stage and the duration is 1-3 years. Confused about past and present. Loss of recognition of familiar people and places Generally incapacitated with severe to total loss of verbal skills. Unable to care for self. Immobility likely. Patients need total support and care, and often die from infections or pneumonia

115 Diagnosis of Alzheimer’s Disease
Alzheimer's disease is usually diagnosed clinically from the patient history, collateral history from relatives, and clinical observations, based on the presence of characteristic neurological and neuropsychological features and the absence of alternative conditions. Advanced medical imaging with computed tomography (CT) or magnetic resonance imaging (MRI), and with single photon emission computer tomography (SPECT) or positron emission tomography (PET) can be used to help exclude other cerebral pathology or subtypes of dementia. The diagnosis can be confirmed with very high accuracy post-mortem when brain material is available and can be examined histologically.

116 Causes of Alzheimer’s Disease
Scientists don’t yet fully understand what causes AD. It is likely that the causes include genetic, environmental, and lifestyle factors. Some drug therapies propose that AD is caused by reduced synthesis of the neurotransmitter acetylcholine. Alzheimer's disease is characterized by a build-up of proteins in the brain. Though this cannot be measured in a living person, extensive autopsy studies have revealed this phenomenon. The build-up manifests in two ways: Plaques– deposits of the protein beta-amyloid that accumulate in the spaces between nerve cells Tangles – deposits of the protein tau that accumulate inside of nerve cells

117 Neuropathology Alzheimer's disease is characterised by loss of neurons and synapses in the cerebral cortex and certain subcortical regions. This loss results in gross atrophy of the affected regions, including degeneration in the temporal lobe and parietal lobe, and parts of the frontal cortex and cingulate gyrus. Both amyloid plaques and neurofibrillary tangles are clearly visible by microscopy in brains of those afflicted by AD. Plaques are dense, mostly insoluble deposits of amyloid – beta peptides and cellular material outside and around neurons. Tangles (neurofibrillary tangles) are aggregates of the microtubule-associated protein tau which has become hyperphosphorylated and accumulate inside the cells themselves.

118 Treatment Although there is currently no way to cure Alzheimer's disease or stop its progression, researchers are making encouraging advances in Alzheimer's treatment, including medications and non-drug approaches to improve symptom management. Mild/Moderate AD: Cholinesterase inhibitors increase the levels of acetylcholine in the brain, which plays a key role in memory and learning. This kind of drug postpones the worsening of symptoms for 6 to 12 months in about half of the people who take it. Cholinesterase inhibitors most commonly prescribed for mild to moderate Alzheimer's disease include Aricept (donezepil HCL), Exelon (rivastigmine), and Razadyne (galantamine).

119 Continued Moderate/Severe AD:
Namenda (memantine) regulates glutamate in the brain, which plays a key role in processing information. This drug is used to treat moderate to severe Alzheimer's disease and may delay the worsening of symptoms in some people. It may allow patients to maintain certain daily functions a little longer than they would without the medication.

120 Continued Exelon is a cholinesterase inhibitor that prevents the breakdown of acetylcholine and butyrylcholine in the brain by blocking the activity of two different enzymes. Acetylcholine and butyrylcholine play a key role in memory and learning. When given orally, bioavailability is about 40% in the 3 mg dose. The compound can cross the blood-brain barrier.

121 Continued Aricept (Donepizel)
One of the most widely used drugs to treat the symptoms of Alzheimer's disease. Aricept is FDA-approved for mild, moderate, and severe stages of the disease.

122 Continued Aricept is available in tablet form or an orally disintegrating tablet form, and is commonly started at 5 mg a day. Can cross the blood-brain barrier.

123 Continued Namenda (Memantine)
Namenda is an N-methyl D-aspartate (NMDA) antagonist that regulates the activity of glutamate in the brain. Glutamate plays a key role in memory and learning, but excess glutamate can lead to the disruption of nerve cell communication or nerve cell death.

124 Continued Studies involving Namenda have shown that the drug can slow the rate of decline in thinking and the ability to perform daily activities in individuals who have moderate to severe Alzheimer's disease A dysfunction of glutamatergic neurotransmission is thought to be involved in the etiology of AD. Namenda is available in generic form (memantine HCL).

125 Adverse pharmacological effects
Behavioural Effects (pseudodepression, akinesia, confusion) Neurological Effects (parkinsonism, akathisia, dystonia, tardive dyskinesia) Autonomic Effects (orthostatic hypotension, impaired ejaculation) Metabolic and Endocrine Effects (weight gain, hyperprolactinemia, loss of libedo, impotence) Toxic or allergic effects (agranulocytosis, choleostatic jaundice, clozapine)

126 Adverse pharmacological effects
Ocular complications (thioridazine only) Cardiac toxicity (Thioridazine T wave abnormality) Neuroleptic Malignant Syndrome (life threatening, marked muscle rigidity, sweating, fever, autonomic instability, blood pressure, heart rate, muscle breakdown, CV collapse, arrhythmias mortality = 5-12%

127 Pharmacological effects
Effects on dopamine systems i. Mesolimbic/ mesocortical ii. Nigrostriatal iii. Tuberoinfundibular Dopamine receptors and their effects i. D1/D5 ii. D2/D3/D4 family

128

129 Drug Combinations Combining antipsychotic drugs confounds evaluation of the efficacy of the drugs being used. Use of combinations, however, is widespread, with more emerging experimental data supporting it. Tricyclic antidepressants or, more often, SSRIs may be used with antipsychotics for clear symptoms of depression complicating schizophrenia. Lithium or valproic acid is sometimes added to antipsychotic agents with benefit to patients who do not respond to the latter drugs alone. Clozapine plus lamotrigine developed here in Psychiatry. It is uncertain whether such instances represent misdiagnosed cases of mania or schizoaffective disorder. Sedative drugs may be added for relief of anxiety or insomnia not controlled by antipsychotics.


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