Psychotic Disorders PDF

PSYCHOTIC DISORDERS Dr. Mohammed Ridha M. B. Ch. B., F.I.C.M.S. (Psych.) Psychosis is a general term used to describe a distorted perception of reality. Poor reality testing may be accompanied by delusions, perceptual disturbances (hallucinations), and/or disorganized thinking/...

PSYCHOTIC DISORDERS Dr. Mohammed Ridha M. B. Ch. B., F.I.C.M.S. (Psych.) Psychosis is a general term used to describe a distorted perception of reality. Poor reality testing may be accompanied by delusions, perceptual disturbances (hallucinations), and/or disorganized thinking/ behavior. Psychosis can be a symptom of schizophrenia, mania, depression, delirium, and dementia, and it can be substance or medication-induced. DELUSIONS Delusions are fixed, false beliefs that remain despite evidence to the contrary and cannot be accounted for by the cultural background of the individual. They can be categorized as either bizarre or nonbizarre. A nonbizarre delusion is a false belief that is plausible but is not true. Example: “The neighbors are spying on me by reading my mail.” A bizarre delusion is a false belief that is impossible. Example: “A Martian fathered my baby and inserted a microchip in my brain.” Delusions can also be categorized by theme: Delusions of persecution/paranoid delusions: Irrational belief that one is being persecuted. Example: “The CIA is after me and tapped my phone.” Ideas of reference: Belief that cues in the external environment are uniquely related to the individual. Example: “The TV characters are speaking directly to me.” Delusions of control: Includes thought broadcasting (belief that one’s thoughts can be heard by others) and thought insertion (belief that others’ thoughts are being placed in one’s head). Delusions of grandeur: Belief that one has special powers beyond those of a normal person. Example: “I am the all-powerful son of God and I shall bring down my wrath on you if I don’t get my way.” Delusions of guilt: Belief that one is guilty or responsible for something. Example: “I am responsible for all the world’s wars.” Somatic delusions: Belief that one is infected with a disease or has a certain illness. Perceptual Disturbances Illusion: Misinterpretation of an existing sensory stimulus (such as mistaking a shadow for a cat). Hallucination: Sensory perception without an actual external stimulus. Auditory: Most commonly exhibited by schizophrenic patients. Visual: Occurs but less common in schizophrenia. May accompany drug intoxication, drug and alcohol withdrawal, or delirium. Olfactory: Usually an aura associated with epilepsy. Tactile: Usually secondary to drug use or alcohol withdrawal. Formal Thought Disorders(abnormal thought Processes) Thought process differs from thought content in that it does not describe what the person is thinking but rather how the thoughts are formulated, organized, and expressed. A patient can have normal thought process with significantly delusional thought content. Conversely, there may be generally normal thought content but significantly impaired thought process. Normal thought process is typically described as linear, organized, and goal directed. Circumstantiality: Overinclusion of trivial or irrelevant details that impede the sense of getting to the point. Tangentiality: In response to a question, the patient gives a reply that is appropriate to the general topic without actually answering the question. Example: Doctor: "Have you had any trouble sleeping lately?" Patient: "I usually sleep in my bed, but now I'm sleeping on the sofa. “ Clang associations: Thoughts are associated by the sound of words rather than by their meaning (e.g. “My car is red. I’ve been in bed. It hurts my head.”). Derailment (Synonymous with loose associations.): A breakdown in both the logical connection between ideas and the overall sense of goal directedness. The words make sentences, but the sentences do not make sense. Word salad: Incoherent collection of words. Flight of ideas: A succession of multiple associations so that thoughts seem to move abruptly from idea to idea; often (but not invariably) expressed through rapid, pressured speech. Neologism: The invention of new words or phrases or the use of conventional words i n idiosyncratic ways. Perseveration: Repetition of out of context words, phrases, or ideas. Echolalia: Repetition of the interviewer’s words or phrases. Thought blocking: A sudden disruption of thought or a break in the flow of ideas. Differential Diagnosis of Psychosis Psychotic disorder due to another medical condition Substance/Medication-induced psychotic disorder Delirium/Dementia Bipolar disorder, manic/mixed episode Major depression with psychotic features Brief psychotic disorder Schizophrenia Schizophreniform disorder Schizoaffective disorder Delusional disorder PSYCHOTIC disorder due to another Medical Condition Medical causes of psychosis include: 1. Central nervous system (CNS) disease (cerebrovascular disease, multiple sclerosis, neoplasm, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, tertiary syphilis, epilepsy [often temporal lobe], encephalitis, prion disease, neurosarcoidosis, AIDS). 2. Endocrinopathies (Addison/Cushing disease, hyper/hypothyroidism, hyper/ hypocalcemia, hypopituitarism). 3. Nutritional/Vitamin deficiency states (B12, folate, niacin). 4. Other (connective tissue disease [systemic lupus erythematosus, temporal arteritis], porphyria). DSM-5 criteria for psychotic disorder due to another medical condition include: ▪ Prominent hallucinations or delusions. ▪ Symptoms do not occur only during an episode of delirium. ▪ Evidence from history, physical, or lab data to support another medical cause (i.e., not psychiatric). Substance/Medication-induced psychotic disorder Prescription medications that may cause psychosis in some patients include anesthetics, corticosteroids, antiparkinsonian agents, anticonvulsants, antihistamines, anticholingerics, digitalis, methylphenidate, and chemotherapeutic agents. Substances such as alcohol, cocaine, hallucinogens (LSD, Ecstasy), cannabis, benzodiazepines, barbiturates, inhalants, and phencyclidine (PCP) can cause psychosis, either in intoxication or withdrawal. DSM-5 Criteria ▪ Hallucinations and/or delusions. ▪ Symptoms do not occur only during episode of delirium. ▪ Evidence from history, physical, or lab data to support a medication or substance- induced cause.  Schizophrenia Schizophrenia is usually discussed as a single disease but it probably comprises a group of disorders along a spectrum with heterogeneous etiologies and is characterized by disturbances in cognition, emotion, perception, thinking, and behavior. Schizophrenia is well established as a brain disorder, with structural and functional abnormalities visible in neuroimaging studies and a genetic component as seen in twin studies. Classically, patients with schizophrenia are described as having poor insight into the nature and the severity of their disorder. The so-called lack of insight is associated with poor compliance with treatment. The disorder is usually chronic, with a course encompassing a prodromal phase, an active phase, and a residual phase. The active phase has symptoms such as hallucinations, delusions, and disorganized thinking. The prodromal and residual phases are characterized by attenuated forms of active symptoms, such as odd beliefs and magical thinking, as well as deficits in self- care and interpersonal relatedness. Symptoms of schizophrenia often present in three phases: Prodromal: Decline in functioning that precedes the first psychotic episode. The patient may become socially withdrawn and irritable. He or she may have physical complaints, declining school/work performance, and/or newfound interest in religion or the occult. Active: Perceptual disturbances, delusions, and disordered thought process/content. Residual: Occurs following an episode of active psychosis. It is marked by mild hallucinations or delusions, social withdrawal, and negative symptoms. In general, the symptoms of schizophrenia are broken up into three categories: Positive symptoms: Hallucinations, delusions, bizarre behavior, disorganized speech. These tend to respond more robustly to antipsychotic medications. Negative symptoms: Flat or blunted affect, anhedonia, apathy, alogia, and lack of interest in socialization. These symptoms are comparatively more often treatment resistant and contribute significantly to the social isolation of schizophrenic patients. Cognitive symptoms: Impairments in attention, executive function, and working memory. These symptoms may → poor work and school performance. History of Schizophrenia 1852—Schizophrenia was first formally described by Belgian psychiatrist Benedict Morel, who called it démence précoce. 1896—Emil Kraepelin, a German psychiatrist, applied the term dementia praecox to a group of illnesses beginning in adolescence that ended in dementia. 1911—Swiss psychiatrist Eugen Bleuler introduced the term schizophrenia. No signs or symptoms are pathognomonic; instead, a cluster of characteristic findings indicates the diagnosis. He introduced the concept of the fundamental symptoms, called the four A’s: (1) associational disturbances, (2) affective disturbances, (3) autism, and (4) ambivalence.  1959—German psychiatrist Kurt Schneider proposed the concept of first-rank symptoms (FRS) of schizophrenia, According to Schneider, these symptoms are particularly prevalent in severe psychotic disorders and hold great importance for the diagnosis of schizophrenia.it has been claimed that FRS may also be found in the nonschizophrenic conditions, and therefore, they are not specific or diagnostic for schizophrenia. Delusional perception: Normal perception has a private, illogical meaning. Somatic passivity: Experience of bodily sensations (including actions, thoughts, or emotions) imposed by external agency. Thought broadcasting: The patient’s thoughts escape into the outside world and are experienced by others. Thought withdrawal: The patient’s thoughts are being removed by an external force. Thought insertion: The patient’s thoughts are being inserted by an external force. Running commentary: Voices commenting on one’s actions, Voices describe the patient’s activities as they occur. Thought echo: Audible thoughts, Voices speaking the patient’s thoughts aloud. Third person auditory hallucinations: Voices arguing The patient hears two or more voices, talking to each other, in his or her head. EPIDEMIOLOGY Schizophrenia affects approximately 0.5–1% of people over their lifetime. Men and women are equally affected but have different presentations and outcomes: ▪ Men tend to present in early to mid-20s ▪ Women present in late 20s ▪ Men tend to have more negative symptoms and poorer outcome compared to women. Schizophrenia rarely presents before age 15 or after age 55. There is a strong genetic predisposition: ▪ 46% concordance rate among monozygotic twins ▪ 40% risk of inheritance if both parents have schizophrenia ▪ 12% risk if one first-degree relative is affected Etiological theories A. Genetic: Genetic factors account for the majority of liability to schizophrenia. Heritability estimates range from 60% to 80%. It is likely that an individual needs to have several genes ‘of small effect’ that interact with each other and with time-specific exposure to other environmental risk factors. Schizophrenia liability based on affected relatives B. Biologic ✓ Neurochemical abnormality hypotheses Dopaminergic overactivity Glutaminergic hypoactivity Serotonergic (5-HT) overactivity Alpha-adrenergic overactivity Gamma-aminobutyric acid hypoactivity ✓ The neurodevelopmental hypothesis Some authors hypothesize that schizophrenia may be a disorder of neurodevelopment, based on the following: Excess of obstetric complications in those who develop the disorder. Affected subjects have motor and cognitive problems which precede the onset of illness. Schizophrenic subjects have abnormalities of the cerebral structure at first presentation. Evidence of excessive synaptic pruning during adolescence/ early adulthood. C. Psychosocial and environmental ✓ Family factors: Patients whose families have high levels of expressed emotion (EE) have higher relapse rate than those whose families have low EE levels. EE has been defined as any overly involved, intrusive behavior, be it hostile and critical or controlling and infantilizing. Relapse rates are better when family behavior is modified to lower EE. ✓ Environmental factors: The following have been associated with an risk of schizophrenia: Complications of pregnancy, delivery, and the neonatal period. Delayed walking and neurodevelopmental difficulties. Early social services contact and disturbed childhood behaviour. Severe maternal malnutrition. Maternal influenza in pregnancy and winter births. Degree of urbanization at birth. Use of cannabis, especially during adolescence. The neurodevelopmental model of schizophrenia Diagnosis, Signs, and Symptoms According to the fifth edition of the Diagnostic Statistical Manual of Mental Disorders (DSM-5) at least two of the following five signs or symptoms must be present for at least 1 month: (1) Hallucinations; (2) delusions; (3) disorganized speech; (4) disorganized behavior; or (5) negative symptoms. The signs and symptoms should be present for at least 6 months for the disorder to be confirmed. DSM-5 Criteria Two or more of the following must be present for at least 1 month: 1. Delusions 2. Hallucinations 3. Disorganized speech 4. Grossly disorganized or catatonic behavior 5. Negative symptoms ❖ Note: At least one must be 1, 2, or 3. Must cause significant social, occupational, or self-care functional deterioration. Duration of illness for at least 6 months (including prodromal or residual periods in which the above full criteria may not be met). Symptoms not due to effects of a substance or another medical condition. This patient wore suits too large for him in the delusional belief that he would appear taller to others. This patient had an artificial eye that he believed had special powers when removed from the socket. A symbolic representation of the strange perceptions of the schizophrenia patient.  Patients with schizophrenia live in a state of chronic anxiety and fear. The environment is seen as hostile and threatening as symbolized in this illustration. Negative symptoms (The 5 A’s of schizophrenia ): 1. Anhedonia 2. Affect (flat) 3. Alogia (poverty of speech) 4. Avolition (apathy) 5. Attention (poor) Types of schizophrenia A. Paranoid type Characterized mainly by the presence of delusions of persecution or grandeur and auditory hallucinations. No formal thought disorders, no flat or grossly inappropriate affect, no grossly disorganized behavior. Intelligence remains intact. Most common form. Personality relatively preserved. B. Disorganized type (hebephrenia) Characterized by marked regression to primitive, disinhibited, and chaotic behavior. Incoherence, marked loosening of associations, flat or grossly inappropriate affect, pronounced thought disorder. Early onset, Poor prognosis, Premorbid schizoid or schizotypal personality. C. Catatonic type Classic feature is a marked disturbance in motor function called waxy flexibility. May involve rigidity, stupor, posturing, echopraxia; patients may hold awkward positions for long periods of time. Speech disturbances such as echolalia or mutism may occur. D. Undifferentiated type Prominent delusions, hallucinations, incoherence, or grossly disturbed behavior. Does not meet the criteria for paranoid, catatonic, or disorganized type. E. Residual type Absence of prominent delusions, hallucinations, incoherence, or grossly disorganized behavior. Continuing evidence of the disturbance through two or more residual symptoms (e.g., emotional blunting, social withdrawal). Pathophysiology of schizophrenia A. Neuropathology. No consistent structural defects; changes noted include decreased number of neurons, increased gliosis, and disorganization of neuronal architecture. There is degeneration in the limbic system. Abnormal functioning in basal ganglia and cerebellum may account for movement disorders in schizophrenic patients. B. Brain imaging Some patients may have cortical atrophy; enlargement of the lateral and third ventricle; these abnormal CT findings may correlate with the presence of negative symptoms and poor premorbid history. Ventricles in MZ twins with schizophrenia are larger than those of unaffected siblings. Reduced volume of hippocampus, amygdala, and parahippocampal gyrus. Decreased metabolism of the dorsolateral prefrontal cortex. In some patients, decreased frontal and parietal lobe metabolism, relatively high rate of posterior metabolism, and abnormal laterality. Differential Diagnosis of schizophreia Psychotic disorder due to another medical condition Substance/Medication-induced psychotic disorder Delirium/Dementia Bipolar disorder, manic/mixed episode Major depression with psychotic features Brief psychotic disorder Schizophreniform disorder Schizoaffective disorder Delusional disorder Personality disorders Factitious disorder and malingering Pervasive developmental disorders (e.g., autistic disorder) Intellectual disability Shared cultural beliefs Course and Prognosis ▪ Classically, the course of schizophrenia is one of deterioration over time, with acute exacerbations superimposed on a chronic picture. ▪ Vulnerability to stress is lifelong. ▪ Postpsychotic depressive episodes may occur in the residual phase. Other comorbidities include substance use disorders, obsessive compulsive disorder. ▪ Relapse rates are approximately 40% in 2 years on medication and 80% in 2 years off medication. ▪ Suicide is attempted by 50% of patients; 10% are successful. ▪ Violence is a risk, particularly in untreated patients. ▪ The risk for sudden death and medical illness is increased, and life expectancy is shortened. In terms of overall prognosis, some investigators have described a loose rule of thirds: approximately one third of patients lead somewhat normal lives, one- third continue to experience significant symptoms but can function within society, and the remaining one- third are markedly impaired and require frequent hospitalization. Approximately 10% of this final third of patients require long-term institutionalization. In general, women have a better prognosis than do men. Features Weighting Toward Good or Poor Prognosis in Schizophrenia management of the schizophrenia Clinical management of the schizophrenic patient may include hospitalization and antipsychotic medication in addition to psychosocial treatments, such as behavioral, family, group, individual, and social skills and rehabilitation therapies. Indications for hospitalization include: posing a danger to others, suicidality, severe symptomatology leading to poor self-care or risk for injury secondary to disorganization, diagnostic evaluation, failure to respond to treatment in less restrictive settings, complicating comorbidities, and the need to alter complex drug treatment regimens. A. Pharmacologic. The antipsychotics include the first-generation dopamine receptor antagonists and the second-generation agents such as serotonin–dopamine antagonists (SDAs). After a single episode of schizophrenia, antipsychotic medication is continued for 1 or 2 years. It is generally recommended that multiepisode patients receive maintenance treatment for at least 5 years, and many experts recommend pharmacotherapy on an indefinite basis. Medication is often given in depot form if there are concerns around poor adherence. B. Electroconvulsive therapy (ECT). Can be effective for acute psychosis and catatonic subtype. Patients in whom the illness has lasted less than 1 year are most responsive. ECT is a promising treatment for refractory positive symptoms. It has been shown to have synergistic efficacy with antipsychotic drugs. C. Psychosocial. Like: Family therapy, Supportive psychotherapy and Social skills training. Antipsychotic medication alone is not as effective in treating schizophrenic patients as are drugs coupled with psychosocial interventions.  Schizophreniform Disorder Diagnosis and DSM-5 Criteria The diagnosis of schizophreniform disorder is made using the same DSM-5 criteria as schizophrenia. The only difference between the two is that in schizophreniform disorder the symptoms have lasted between 1 and 6 months, whereas in schizophrenia the symptoms must be present for > 6 months. Prognosis One-third of patients recover completely; two-thirds progress to schizoaffective disorder or schizophrenia. Treatment Hospitalization (if necessary), course of antipsychotics for psychosis, and supportive psychotherapy.  Schizoaffective Disorder The diagnosis of schizoaffective disorder is made in patients who: Meet criteria for either a major depressive or manic episode during which psychotic symptoms consistent with schizophrenia are also met. Delusions or hallucinations for 2 weeks in the absence of mood disorder symptoms (this criterion is necessary to differentiate schizoaffective disorder from mood disorder with psychotic features). Mood symptoms present for a majority of the psychotic illness. Prognosis Worse with poor premorbid adjustment, slow onset, early onset, predominance of psychotic symptoms, long course, and family history of schizophrenia. Schizoaffective patients have a better prognosis than schizophrenic patients and a worse prognosis than mood disorder patients. Treatment Hospitalization (if necessary) and supportive psychotherapy. Medical therapy: Antipsychotics (second-generation medications may target both psychotic and mood symptoms); mood stabilizers, antidepressants, or electroconvulsive therapy (ECT) may be indicated for treatment of mood symptoms.  Brief Psychotic Disorder Diagnosis and DSM-5 Criteria Patient with psychotic symptoms as in schizophrenia; however, the symptoms last from 1 day to 1 month, and there must be eventual full return to premorbid level of functioning. Symptoms must not be due to the effects of a substance (drug or medication) or another medical condition. This is a rare diagnosis, much less common than schizophrenia. It may be seen in reaction to extreme stress such as bereavement, sexual assault, etc. Prognosis By definition, course of the disorder is less than 1 month. Recovery is up to 80% with treatment. Treatment Brief hospitalization (usually required for workup, safety, and stabilization), supportive therapy, course of antipsychotics for psychosis.  Delusional Disorder Disorder in which the primary or sole manifestation is a nonbizarre delusion that is fixed and unshakable. The delusions are usually about situations that can occur and are possible in real life, such as being followed, infected, or loved at a distance. Delusional disorder occurs more often in middle-aged or older patients (after age 40). Delusions last at least 1 month and are well systematized and nonbizarre as opposed to fragmented and bizarre. The patient’s emotional response to the delusional system is congruent with and appropriate to the content of the delusion. The personality remains intact or deteriorates minimally. Under nonstressful circumstances, patients may be judged to be without evidence of mental illness. Types of Delusions Erotomanic type: Patient believes that someone, usually of higher socioeconomic status, is in love with him or her. Criteria can include (1) a delusional conviction of amorous communication; (2) object of much higher rank; (3) object being the first to fall in love; (4) object being the first to make advances; (5) sudden onset (within a 7-day period); (6) object remains unchanged; (7) patient rationalizes paradoxical behavior of the object; (8) chronic course; and (9) absence of hallucinations. More common in women. Accounts for stalking behavior.  Grandiose type: Delusions of having great talent. Somatic type: Physical delusions. Persecutory type: Delusions of being persecuted. Jealous type: Delusions of unfaithfulness. Shared delusional disorder (also known as folie à deux). Two people have the same delusional belief. Most common in mother–daughter relationships. Epidemiology The mean age of onset is about 40 years. A slight preponderance of female patients exists. Men are more likely to develop paranoid delusions than women, who are more likely to develop delusions of erotomania. Prognosis Better than schizophrenia with treatment: ▪ > 50%: Full recovery ▪ > 20%: ↓ symptoms ▪ < 20%: No change Treatment Difficult to treat, especially given the lack of insight and impairment. Antipsychotic medications are recommended despite somewhat limited evidence. Supportive therapy is often helpful, but group therapy should be avoided given the patient’s suspiciousness. Comparing Time Courses and Prognoses of Psychotic Disorders Time Course: ▪< 1 month—brief psychotic disorder ▪1–6 months—schizophreniform disorder ▪> 6 months—schizophrenia Prognosis from Best to Worst: Mood disorder with psychotic features > schizoaffective disorder > schizophreniform disorder > schizophrenia.  Antipsychotic Medications First-generation (or typical) antipsychotic medications: These are primarily dopamine (mostly D2) antagonists. Treat positive symptoms with minimal impact on negative symptoms. Side effects include extrapyramidal symptoms, neuroleptic malignant syndrome, and tardive dyskinesia. Chlorpromazine (Largactil): with mainly anti-adrenergic and antihistaminergic side effects, including pronounced sedation, moderate antimuscarinic effects, and moderate EPSEs. Fluphenazine (Modecate) available in decanoate (long-acting) form and Trifluoperazine (Stelazine) :potent antipsychotics but tend to produce troublesome EPSEs, particularly at higher doses. They have limited sedative properties. Haloperidol (Serenace ) available in depot (long-acting) injections and as injectable forms for management of acute behavioural disturbance(Haldol): high potency, troublesome EPSEs. Flupentixol (Depixol, Fluanxol) available as depot and Zuclopenthixol (Clopixol) available in injectable forms as acetate..both have moderate sedative, antimuscarinic, and extra-pyramidal effects. Others: Mesoridazine (Serentil) Perphenazine (Trilafon) Thioridazine (Mellaril) Side effects of antipsychotic medications: 1. Extra-pyramidal side effects Acute dystonia Contraction of muscle group to maximal limit, typically sternocleidomastoid and tongue, although can be widespread (e.g. opisthoclonus); eye muscle involvement (e.g. oculogyric crisis) may occur. Virtually always distressing and preceded by increasing agitation. Treatment: Parenteral antimuscarinic (e.g. procyclidine 10mg iv). Parkinsonism Tremor, rigidity, and bradykinesia occurring >1wk after administration. Treatment: Consider dose reduction/use of oral antimuscarinic (e.g. procyclidine 5mg tds). Extra-pyramidal side effects (cont…) Akathisia Restlessness, usually of lower limbs, and a drive to move. Occurs usually >1mth after initiation of antipsychotic drug. Treatment Propranolol and BDZs may be helpful. Symptoms can be notoriously difficult to treat. Tardive dyskinesia (TD) Continuous, slow writhing movements (i.e. athetosis) and sudden involuntary movements, typically of the oral– lingual region (chorea). Symptoms of TD tend to be irreversible. Treatment: Although a consequence of antipsychotic treatment, there is little evidence that a reduction in the dose of antipsychotic improves symptoms in the short or long term. Vitamin E may prevent deterioration but does not improve established symptoms 2. Anticholinergic symptoms (especially low- potency first-generation antipsychotics and atypical antipsychotics): Dry mouth, constipation, blurred vision, hyperthermia. Treatment: As per symptom (eye drops, stool softeners, etc.) 3. Neuroleptic malignant syndrome (typically high- potency first-generation antipsychotics): Change in mental status, autonomic instability (high fever, labile blood pressure, tachycardia, tachypnea, diaphoresis), “lead pipe” rigidity, elevated creatine phosphokinase (CPK) levels, leukocytosis, and metabolic acidosis. A medical emergency that requires prompt withdrawal of all antipsychotic medications and immediate medical assessment and treatment. 4. Others: Prolonged QTc interval and other electrocardiogram changes, hyperprolactinemia (→ gynecomastia, galactorrhea, amenorrhea, diminished libido, and impotence), ophthalmologic conditions (thioridazine may cause irreversible retinal pigmentation at high doses; deposits in lens and cornea may occur with chlorpromazine), dermatologic conditions (such as rashes and photosensitivity). Second-generation (or atypical) antipsychotic medications: These antagonize serotonin receptors (5-HT2) as well as dopamine (D2) receptors. Research has shown no significant difference between first- and second generation antipsychotics in efficacy. The selection requires the weighing of benefits and risks in individual clinical cases. Lower incidence of extrapyramidal side effects, but ↑ risk for metabolic syndrome. Medications should be taken for at least 4 weeks before efficacy is determined. Clozapine is reserved for patients who have failed multiple antipsychotic trials due to its ↑ risk of agranulocytosis. Olanzapine (Zyprexa) Risperidone (Risperdal) Paliperidone (Invega) Quetiapine (Seroquel) Clozapine (Clozaril) Aripiprazole (Abilify) Amisulpride (Solian) Lurasidone (Latuda) Therapeutic indications. Second-generation drugs are effective for initial and maintenance treatment of psychosis in schizophrenia and schizoaffective disorders in both adults and adolescents. They are also effective in the acute treatment of manic or mixed episodes in bipolar disorder, bipolar depression, adjunctive therapy to antidepressants for MDD and for psychoses of all types—secondary to head trauma, dementia, and drug-induced psychosis. Aripiprazole (Abilify), quetiapine (Seroquel), and brexpiprazole (Rexulti) are the only medications approved by the FDA for add-on treatment to antidepressants for adults with MDD. Olanzapine and fluoxetine combination is indicated for use in treatment-resistant depression. Other SDAs are in the process of receiving this indication and extending it to GAD as well. Clozapine : general guidelines Clozapine, is an SGA. Shortly after its introduction to clinical practice in the mid-1970s, it was withdrawn because of several episodes of fatal agranulocytosis in patients on treatment. It was thought to have special efficacy in treatment-resistant schizophrenia. In the CATIE trial, clozapine was shown to be superior in both treatment response (positive and negative symptoms) and compliance for patients who failed to improve on an SGA. Recent evidence from a meta-analysis found it to be superior for treatment-refractory disorder but recommended that if there is no response by 6mths, medications with lower adverse reactions should be considered. NICE guideline NICE (2014) recommends offering clozapine ‘to people with schizophrenia whose illness has not responded adequately to treatment despite the sequential use of adequate doses of at least 2 different antipsychotic drugs’ (at least one of which was a non-clozapine SGA). Initiation of treatment and monitoring A normal leucocyte count [white cell count (WCC) >3500/mm3, neutrophils >2000/mm3) must precede treatment initiation. FBCs must be repeated at weekly intervals for 18wks and then fortnightly until 1yr. Blood monitoring should continue monthly indefinitely thereafter. STOP clozapine immediately If the WCC is