The approach to schizophrenia and early phases of psychotic disorder demands a careful selection from the different types of interventions available, their proper articulation, as well as the most appropriate scope of intervention.

To address this issue, studies such as Falloon’s, aimed at the implementation of treatments integrated with scientific evidence, have been developed. ⁷¹ According to this author, any person with a schizophrenic disorder should receive a combination of optimum antipsychotic treatment, educational strategies aimed at the patient and his/her environment, cognitive behavioural strategies to improve occupational and social objectives, reduction of residual symptoms and assertive home-based care.

In the following section we present the analysis of different types of intervention and a study on the different care settings offered in the community.

6.1. Pharmacological intervention

Pharmacological treatments are usually an essential element of treatment in patients with schizophrenia or initial psychotic episodes. Drugs are used to treat acute episodes, to prevent future episodes and to improve symptoms in between episodes. Antipsychotic drugs are the main pharmacological treatment for these patients. However, other drugs, such as mood stabilizers and other coadjuvant medications, are also useful in certain patient subgroups.^2-4,72

6.1.1. Antipsychotic drugs

The main medications for the treatment of schizophrenia and other psychotic disorders are antipsychotic drugs, which were introduced into clinical practice during the 1950s. Due to their characteristics, effects on psychotic symptoms and side effect profiles, they have been classified into two large groups: first-generation or conventional antipsychotics, and second-generation or atypical antipsychotics. The analysis of both groups, which is presented below, has acknowledged the considerations on pharmacological treatments included in the different clinical practice guidelines examined, as well as those that appear in the Therapeutic Prescription Guideline (TPG) with information regarding authorized drugs in Spain, the Spanish adaptation of the British National Formulary, published by the Spanish Drug and Health Product Agency (2006)^b . The TPG has been especially acknowledged in terms of the dosage of the different drugs assessed, both in the elaboration of the text and in the different prescription and comparative tables developed. In this sense, and with regard to the recommendation regarding doses over the indicated high limit, it is understood that “unless otherwise specified, the doses indicated are those that have been authorized; in other words, higher doses are not authorized”. ⁷³

A) First generation (or conventional) antipsychotics

First generation antipsychotics encompass a series of pharmaceutical specialities that are characterized by treating psychotic symptoms. The following first generation antipsychotics are currently authorized in Spain: chlorpromazine, clotiapine, haloperidol, levomepromazine, perphenazine, periciazine, pimozide, sulpiride, thioproperazine, trifluoperazine and zuclopenthixol.

These drugs are classified into three groups based on their antipsychotic potency: a) high potency (e.g., haloperidol); b) moderate potency (e.g., perphenazine); c) low potency (e.g., chlorpromazine).

They are effective at reducing most positive symptoms (hallucinations, delusions, odd behaviour), and, to a lesser degree, negative symptoms (apathy, affective flattening, alogia, avolition), when compared to relatively ineffective drugs.

Given that these drugs have a very high safety therapeutic margin, overdosing is rarely fatal if there are no pre-existing medical problems or simultaneous consumption of alcohol or other drugs. In case of overdosing, respiratory depression and hypotension present the highest risk.

Administration can be oral, fast acting intramuscular or long acting depot; the short acting intramuscular preparation achieves maximum concentration faster. Depot medications are especially useful in the maintenance phase (table 3, annex 2).

The effective dose of an antipsychotic drug is closely linked to its affinity for dopamine receptors (especially D₂ receptors) and its tendency to cause extrapyramidal side effects. High potency drugs have a greater affinity for dopamine receptors than low potency drugs do, and require much lower doses.

High potency drugs are prescribed more frequently than low dose drugs (even though they have a higher tendency to produce extrapyramidal side effects), and are administered more safely via intramuscular route as they rarely cause hypotension.⁷⁴ An adequate dose can be obtained in two days. It has been demonstrated that high doses of high potency antipsychotics are not more effective nor have a faster action than moderate doses and are associated with a higher incidence of side effects. ⁷⁴

Low potency drugs produce sedation and orthostatic hypotension and the dose should be gradually increased. They can cause a wide array of side effects, many of them a consequence of the pharmacological effects on neurotransmitter systems in regions other than where the medication is intended to exercise its therapeutic effects.

In the section below there is a brief description of each first generation antipsychotic drug, in conformity with the characteristics and uses as established in the TPG. Posology guidelines are presented in table 4, annex 2. Likewise, a comparative table has been developed for standard dosage intervals for adults based on the recommendations of the TPG⁷³, as well as a comparative table of standard dosage intervals for adults according to the APA’s⁴ and the Canadian Psychiatric Association’s (CPG) CPGs, ² those recommended by the World Federation of Societies of Biological Psychiatry (WFSBP) ^{75, 76} and PORT⁴⁰, and, finally, those from two reference publications in the Spanish setting: RTM-III⁷⁷ and Chinchilla⁷⁸ (table 5, annex 2).

1. Chlorpromazine
   It is also indicated for mania, as brief complementary treatment of severe anxiety, psychomotor agitation, restlessness and violent or dangerously impulsive behaviour.
   The usual maintenance oral dose is 75-300 mg/day depending on the response obtained, with a starting dose of 25 mg, three times a day, or 75 mg at night. The treatment of psychosis requires up to 1 g/day.
   In deep intramuscular injection, dose ranges from 25-50mg every 6-8 hours. This administration route is recommended for acute symptom relief.
2. Clotiapine
   It is indicated for schizophrenia, acute and chronic psychosis, mania and insomnia in psychotic patients.
   It is administered orally, with a starting dose of 120-160 mg at bed time. The maximum dose is 360 mg/day.
   For treatment of insomnia, the dose is 20-60 mg taken at bed time. In this case, the maximum dose is 360 mg/day.
3. Haloperidol
   It is indicated for mania, as brief complementary treatment of severe anxiety, psychomotor agitation, restlessness and violent or dangerously impulsive behaviour.
   Aside from the characteristic precautions and contraindications of conventional antipsychotics, it can also cause subarachnoid haemorrhaging and metabolic disorders such as hypopotasemia, hypocalcemia or hypomagnesemia.
   The most frequent side effects are strange pigmentation and photosensitivity reactions. Its extrapyramidal effects include dystonia and akathisia, especially in patients with thyrotoxicosis, hypoglycemia and inadequate secretion of the antidiuretic hormone, and, rarely, weight loss. It presents less sedative and antimuscarinic or hypotensive effects than other conventional antipsychotics.
   It is administered in oral, intramuscular or intravenous form. The starting oral dose is 1.5-3 mg, 2 to 3 times daily, if the patient has a severe or resistant disorder. In refractory schizophrenia up to 30 mg/day may be required.
   The maintenance dose should be adjusted to the lowest effective dose, 5-10 mg/day, depending on the response obtained. In elderly or weakened people, the initial dose should be half of an adult dose.
   The starting dose for intramuscular or intravenous injection is 2-10 mg, taken every 4-8 hours depending on the response obtained, with a maximum daily dose of 18 mg. Patients with severe disorders sometimes require a starting dose of up to 18 mg.
4. Levomepromazine
   Caution should be exercised with those patients who receive high initial doses. It is recommended that these patients remain in a face up supine position.
   Elderly people have a higher risk of suffering postural hypotension, so this drug is not recommended in outpatients over the age of 50, unless the risk of hypotensive reaction has been assessed.
   One of the most important side effects is an increased sedimentation rate.
   It is administered orally, with a starting dose of 25-50 mg/day taken in divided doses. Dose can be increased based on the patient’s needs. In bedridden patients, the starting dose is 100-20 mg/day, generally taken in three doses. Dosage can be increased, if necessary, up to 1 g/day.
5. Perphenazine
   It is indicated for mania, as brief complementary treatment of severe anxiety, psychomotor agitation, restlessness and violent or dangerously impulsive behaviour.
   Aside from the characteristic precautions and contraindications of conventional antipsychotics, it can also cause agitation and restlessness in elderly people.
   It has a less sedative effect. It produces extrapyramidal side effects, especially dystonia, that are more frequent at higher doses. It may rarely cause systemic lupus erythematous.
   It is administered orally, with a starting dose of 4 mg, 3 times daily, adjusted according to the response obtained. The maximum dose is 24 mg/day.
6. Periciazine
   It has a more sedative effect. There are side effects at the beginning of treatment, such as hypotension, and also respiratory depression.
   It is administered orally, with a starting dose of 75 mg/day, taken in divided doses; dose should be increased each week by 25 mg phases, according to the response obtained. The normal daily maximum dose is 300 mg/day.
   It is also used as brief complementary treatment for severe anxiety, psychomotor agitation and violent or dangerously impulsive behaviour. In these cases the initial recommended dosage is 15-30 mg/day, taken in two separate doses, taking the higher doses at bed time and adjusting dosage according to the response obtained.
7. Pimozide
   It is recommended to perform an ECG before initiating treatment and every year during follow-up. If the QT interval is prolonged, treatment should be reviewed and dosage discontinued or reduced under careful surveillance.
   This drug should not be administered with other antipsychotics, not even those that are long acting, tricyclic antidepressants or drugs that prolong the QT interval, such as certain antipaludics, antiarrhythmics and some antihistaminics, nor with any other drugs that cause electrolyte imbalances (especially diuretics).
   It is contraindicated in people with a past medical history of arrhythmia or congenital prolonged QT.
   The most frequent side effects are severe arrhythmias, glycosuria, and sometimes hyponatremia. It has a less sedative effect.
   The recommended starting dosage is 2mg/day, which should be increased at intervals of no less than a week apart and at 2 to 4 mg increments until satisfactory response is obtained. Normal dosage range is 2-20 mg/day.
   For the treatment of monosymptomatic hypochondriac psychosis and paranoid psychosis, the recommended starting dose is 4 mg/day, which should be increased at intervals of no less than a week apart and at 2 to 4 mg increments, according to the response obtained. Dose should not exceed 16 mg/day.
8. Sulpiride
   Caution should be exercised in the administration of this drug in patients who are excited, agitated or aggressive, given that low doses can aggravate symptoms.
   It is contraindicated in people diagnosed with porphyria.
   The recommended dose range is 200-400 mg/day, two times daily. Maximum dose is 800 mg/day if there are mostly negative symptoms and 2.4 g/day if there are mostly positive symptoms.
9. Thioproperazine:
   It is indicated for patients with schizophrenia, anxiety, delirium and mania.
   The most frequent side effects are pancytopenia, thrombocytopenia, hyperthermia and anorexia.
   It is administered orally and the therapeutic dose range is 30-40 mg/day, taken in 3-4 doses.
10. Trifluoperazine:
    It is indicated as brief complementary treatment of psychomotor agitation, restlessness and violent or dangerously impulsive behaviour.
    The most frequent side effects at doses higher than 6 mg/day are pancytopenia, thrombocytopenia, hyperthermia and anorexia.
    The starting dose is 5 mg, twice daily, or 10 mg once daily in a modified release form; dose should be increased by 5 mg at one week, and thereafter at three day intervals, according to the response obtained.
11. Acetato de zuclopentixol:
    This drug is indicated for brief treatment of acute psychosis, mania or exacerbations of chronic psychosis.
    It is contraindicated in patients diagnosed with porphyria.
    If administration is intramuscular, the recommended mean dose is 50-150 mg in one deep injection into the gluteus maximus muscle or into the external side of the thigh.
    It is recommended to repeat the injection, if necessary, after 2 or 3 days (another dose may be necessary 1-2 days after the first injection). The maximum accumulative dose is 400 mg per cycle, and the number of injections should not exceed four. Treatment should not last longer than two weeks. If maintenance treatment is required, the patient should be switched to an oral antipsychotic to be taken 2-3 days after the last injection or to a longer acting antipsychotic injection (depot) that is administered at the same time together with the last injection of zuclopenthixol acetate.
12. Zuclopenthixol dihydrochloride:
    It is indicated in schizophrenia and other psychoses, especially those associated with agitation, aggressiveness or hostility.
    It is contraindicated in patients diagnosed with porphyria and in patients who present apathy or withdrawal states.
    The most frequent side effects are pollakiuria or urinary incontinence and weight loss (less common than weight gain).
    This drug is administered orally, with a starting dose of 20-30 mg/day, in divided doses. Dose should be increased to a maximum of 150 mg/day, if deemed necessary. The standard maintenance dose range is 20 to 50 mg/day.

Side effects of first generation (or conventional) antipsychotics

Several side effects as presented by the APA’s CPG⁴ are individually described below:⁴

1. Sedation
   Sedation is a very common side effect of first generation antipsychotics. This effect may be related to the antagonist effects of these drugs on histamine, adrenergic and dopamine receptors.
   Sedation is more pronounced in the early phases of treatment because the continuous administration of these drugs increases patient tolerance to sedative effects. In the case of agitated patients, it is possible that the sedative effects of these drugs at the beginning of treatment may present a therapeutic advantage. Persistent sedation, such as day drowsiness and sleeping for hours, can interfere with social, recreational and occupational function. Reducing the daily dose, administering one dose at night instead of several doses throughout the day or using a less sedative antipsychotic drug may be effective at reducing the intensity of sedation.
2. Neurological effects. Extrapyramidal side effects.
   The neurological side effects are: acute extrapyramidal side effects, such as drug-induced Parkinsonism, dystonia and akathisia; chronic extrapyramidal side effects, such as tardive dyskinesia and dystonia, and the neuroleptic malignant syndrome.
   Acute extrapyramidal side effects are signs and symptoms that appear within the first few days and weeks of antipsychotic medication use, are dependent on dose and reversible if dose is reduced or administration is completely discontinued.
   Chronic extrapyramidal side effects are signs and symptoms that appear within months or years of antipsychotic medication use, are not so clearly dependant ton dose and may persist after medication discontinuation.
   Over 60% of patients who receive intensive treatment with a first generation antipsychotic present some type of clinically significant extrapyramidal side effect .^79-81
   Drug-induced Parkinsonism is characterized by the presence of symptoms mimicking idiopathic Parkinson’s disease (rigidity, tremor, akinesia and bradykinesia) and is the most frequent presentation of extrapyramidal side effects. These symptoms appear within the first few days and weeks of antipsychotic medication use and are dose-dependant.
   Akinesia or bradykinesia are characteristic symptoms of drug-induced Parkinsonism that affects both motor and cognitive function.
   In patients with akinesia, depressive symptoms may also be observed; it is the so-called “akinetic depression”.
   Acute dystonia is characterized by spastic contraction of isolated muscle groups. Dystonic reactions occur in 10% of patients who initiate treatment.
   Risk factors include young age, male gender, use of high potency drugs, high doses and intramuscular administration. It frequently occurs after the first doses of medication and in 90% of cases within the first three days.
   It can affect several areas of the body, but most frequently develops in the neck muscles, the larynx, eyes and torso; the terms “torticollis”, “laryngospasm”, “oculogyric crisis” and “opisthotonos” are used to describe the dystonic reactions of specific body regions. These reactions have a sudden onset and cause a great deal of discomfort. In some patients, these reactions, for example the laryngospasm, can be dangerous and even life-threatening.
   These reactions respond quickly to the administration of anticholinergic or antihistaminic medication. Parenteral administration has a quicker effect than oral administration. Oral administration of anticholinergic anti-parkinsons medication can be later used to prevent relapses.
   Akathisia is characterized by somatic agitation, which is manifested subjectively and objectively in 30% of patients treated with first generation antipsychotics, and is less frequent with low potency antipsychotics.
   Patients usually report inner restlessness and the irresistible urge to move several parts of the body.
   In mild akathisia, the patient is able to control body movements, but in more severe forms the patient will not stop walking while standing and is unable to remain seated. This secondary effect is often very uncomfortable and frequently results in poor adherence to antipsychotic treatment; if left untreated, it can cause dysphoria. It can also contribute to aggressive or suicidal behaviour.
   Effective treatments for akathisia include central action β-blockers, propanolol (30-90 mg/day). When these drugs are administered, blood pressure and heart rate should be monitored for different doses.
   The neuroleptic malignant syndrome is characterized by a triad of symptoms: rigidity, hyperthermia and autonomic instability, hypertension and tachycardia. It is associated with elevated blood concentration of creatine-kinase.
   Prevalence is less than 1% of patients treated. Its diagnosis often goes unnoticed and it can be fatal in 5-20% of untreated patients.
   Onset can be sudden, often within the first week or after increasing the dose.
   Risk factors are: acute agitation, young age, male gender, prior neurological incapacity, physical disease, dehydration, fast increase of antipsychotic dose, administration of high potency drugs and intramuscular preparations.
   Treatment with antipsychotics should always be interrupted and supportive treatment provided to maintain hydration and treat fever, as well as cardiovascular, renal and other symptoms. Its treatment requires, in most cases, hospitalization.
   Tardive dyskinesia is a disorder characterized by abnormal hyperkinetic involuntary movements caused by prolonged exposure to antipsychotic medication. It can affect neuromuscular function in any part of the body, but is especially common in the orofacial region.
   Schizophrenia itself can be associated with risk of spontaneous dyskinesia that cannot be distinguished from drug-induced dyskinesia.
   Tardive dyskinesia occurs at an annual rate of 4 to 8% of adult patients treated with this type of antipsychotics.
   Risk factors are: elderly age, antipsychotic-induced Parkinsons symptoms, female gender combined with postmenopausal state, diagnosis of mood disorder (major depressive disorder), concomitant medical diseases (diabetes) and use of high antipsychotic doses.
   Most patients have mild symptoms but 10% present moderate or intense symptoms. A frequent and severe variant of tardive dyskinesia is tardive dystonia, which is characterized by the onset of spastic muscle contractions instead of choreoathetotic movements. Tardive dystonia is often associated with greater distress and physical discomfort.
   The therapeutic options for tardive dyskinesia are to use a second generation antipsychotic or reduce the dose of the currently used drug, in which case there may be an initial increase of dyskinetic symptoms (withdrawal dyskinesia). With prolonged exposure to first generation antipsychotics, without reducing the dose after the onset of tardive dyskinesia, the probability of reversibility decreases but does not disappear.
3. Anticholinergic and antiadrenergic effects
   The side effects of first generation antipsychotics (and, in the case of joint administration, with the anticholinergic side effects of antiparkisonians) can produce a variety of peripheral side effects, such as dry mouth, blurred vision, constipation, tachycardia, urinary retention and thermoregulating effects. Anticholinergic side effects can appear in 10-50% of treated patients. It should be noted that more anticholinergic side effects have been reported with the use of chlorpromazine than with haloperidol.
   Although the majority of anticholinergic side effects are mild and tolerable, this type of effects can be particularly problematic in older patients (e.g., older man with prostatic hypertrophy). The conditions of anticholinergic effects are severe in very few cases.
   Anticholinergic effects are learning and memory disturbances, and impaired, slowed down cognition. The symptoms of anticholinergic toxicity are confusion, delirium, drowsiness and hallucinations. It is more likely that these symptoms appear with drugs whose anticholinergic effects are more potent, or due to the administration of anticholinergic antiparkinson’s drugs, and also in elderly or medically debilitated patients.

Other side effects

Convulsions: First generation antipsychotics can reduce the threshold of convulsion and trigger the onset of widespread tonic-clonic convulsions. The low potency of these antipsychotics is associated with a higher risk. In the case of low potency antipsychotics, convulsion frequency is associated with dose, and higher doses are associated with higher risk. With normal doses, the rate of convulsion is below 1%, although in the case of patients with a history of idiopathic or drug-induced convulsions there is increased risk.

Allergy and skin: Allergic skin reactions are fairly frequent with first generation antipsychotics. Treatment interruption or the administration of an antihistaminic is usually effective at decreasing these symptoms.

Liver: This type of drugs also produces elevated concentration of liver enzymes and cholestatic jaundice. Jaundice has been reported in 0.1 to 0.5% of patients who take chlorpromazine. This side effect usually occurs within the first month of treatment and generally requires treatment interruption.

Ophthalmologic: Pigmentary retinopathies and corneal opacities may develop with the chronic administration of low potency drugs, such as chlorpromazine, especially at high doses (e.g. over 800 mg/day of thioridazine –already withdrawn from the market-). For this reason, patients using these drugs should undergo periodic ophthalmologic exams.

Blood: The administration of antipsychotic drugs can cause side effects on blood, such as leukopoiesis inhibition. This type of effects includes benign leukopenia and agranulocytosis, which is more severe. Chlorpromazine is the cause of benign leukopenia in over 10% of patients and agranulocytosis in 0.32%.

Cardiovascular: The most significant cardiovascular effects are orthostatic hypotension, tachycardia and prolonged QT interval with haloperidol.

Weight gain: Most antipsychotics produce weight gain; up to 40% of treated patients gain weight.

The prevention of weight gain should be a priority, given that many patients have difficulties losing weight. When the patient has gained weight, he/she should be advised to diet and exercise, or be referred to a dietician.

Sexual function: Erectile dysfunction occurs in 23-54% of men. Other effects include ejaculation disorders in men and loss of libido or anorgasmia in both sexes. Furthermore, in certain antipsychotics retrograde ejaculation has been reported, likely as a result of antiadrenergic and antiserotonergic effects. Dose reduction or treatment interruption usually leads to symptom reduction or disappearance. If it is not possible to reduce the dose or administer an alternative drug, yohimbine or cyproheptadine can be used.

Pharmacological interaction of first generation (or conventional) antipsychotics

Numerous pharmacological interactions that result in significant clinical effects can occur in patients who receive antipsychotic medication. Certain heterocyclic antidepressants, most selective serotonin reuptake inhibitors (SSRIs), some betablockers and cimetidine can increase blood concentration of antipsychotics and side effects. On the other hand, barbiturates and carbamazepine decrease blood concentration by acting upon cytochrome P-450 enzymes.⁴

B) Second generation (or atypical) antipsychotics

At present the following second generation antipsychotics are authorized in Spain: clozapine, risperidone, olanzapine, paliperidone, sertindole, quetiapine, ziprasidone, amisulpride and aripiprazole.

In this section each second generation antipsychotic has been described. Posology guidelines presented in the TPG have also been included (table 6, annex 2)⁷³, as well as a comparative table for normal dosage intervals for adults according to recommendations from the TPG,⁷³ the APA’s CPG⁴ and the CPG,² those recommended by the WFSBP^{75, 76} and PORT⁴⁰, and finally, those from two consultation publications in Spain: RTM-III⁷⁷ and Chinchilla⁷⁸ (table 7, annex 2).

In regards to the side effects of atypical antipsychotics (AASEs) the TPG lists weight gain, dizziness, postural hypotension (especially during the initial dose adjustment) which can be associated with reflex syncope or tachycardia of some patients, extrapyramidal symptoms (overall, mild and transitory, which respond to dose reduction or to an antimuscarinic drug) and, sometimes, tardive dyskinesia after long-term treatment (medication should be discontinued at the onset of the first signs). Hyperglycaemia and, sometimes, diabetes can occur, especially with clozapine and olanzapine; weight and blood glucose monitoring enable the detection of hyperglycemias. The neuroleptic malignant syndrome has been rarely reported.

1. Amisulpride
   This drug presents high selective affinity for D₂ and D₃ receptors; at low doses (50-300 mg) it is a presynaptic D₂, D₃ antagonist with efficacy on negative symptoms, and at high doses (400-1200 mg) it is a postsynaptic D₂ antagonist, with efficacy on positive symptoms.⁸²
   Dosage range is 400-800 mg/day, taken in two doses. The most frequent side effects are extrapyramidal (dyskinesia, akathisia) and present low incidence, with weight gain and prolactin increase similar to that of other neuroleptic drugs.⁶⁹ Aside from AASEs, insomnia, anxiety, agitation, drowsiness, digestive disorders such as constipation, nausea, vomiting and dry mouth and, occasionally, bradycardia, have been reported; convulsions have rarely been reported.⁷³
   QT may increase and lead to the risk of ventricular arrhythmias (cardiologic study).⁷⁸ Its administration is oral.
2. Aripiprazole
   First partial agonist with affinity for D₂ receptors. It is a partial 5HT1A agonist, 5HT₂A antagonist and modulator of the DA/5HT system, and is effective for positive, negative and mood symptoms, reducing extrapyramidal symptoms and excitability-hostility.⁸³
   It has a low risk of side effects and extrapyramidal effects, does not produce weight gain or psychosexual effects (does not affect prolactin), nor does it alter the metabolism of cholesterol, triglycerides or glucose. It does not present QT disturbances. It may produce headaches, insomnia or agitation-anxiety. ⁷⁸ Aside from AASEs, nausea, vomiting, dyspepsia, constipation, akathisia, drowsiness, tremors, asthenia, blurred vision; more rarely tachycardia, convulsive crises; very rarely hypersialorrhea, pancreatitis, chest pain, agitation, speech disorder, cramps, rhabdomyolysis, priapism and altered thermoregulation.⁷³
   In agitated patients this drug may be combined with benzodiazepines.⁸⁴ It is administered orally (tablets and orally disintegrating tablets) with a dose range of 10-15 mg/day.
3. Clozapine
   This drug presents antagonist activity for D₁ and D₂ dopamine receptors, as well as for 5-HT, adrenergic, histamine and muscarinic receptors. It is the antipsychotic drug with the lowest incidence of extrapyramidal side effects and may produce agranulocytosis that may be fatal in 1% of patients.
   A multicenter RCT demonstrated that it was effective in patients resistant to first generation antipsychotic treatment and in patients who do not tolerate the extrapyramidal effects of these drugs, especially tardive dyskinesia.⁸⁵ In these patients, it was effective at reducing both positive and negative symptoms (level of scientific evidence lb).⁸⁶
   Therapeutic doses range from 200-450 mg/day with a starting dose of 12.5 mg, once or twice daily; it should be slowly increased at daily increments of 25-50 mg/day initially and subsequently at weekly increments of 50-100 mg. The maximum dose is 900 mg/day.
   It is used when there is resistance to two antipsychotics from a different family. Its use is contraindicated in patients with prior hypersensitivity to clozapine; a history of drug-induced granulocytopenia/agranulocytosis; white blood cell count lower than 3,500/mm³; altered bone marrow function; alcoholic, toxic psychoses and comatose states; respiratory collapse and/or depression of the central nervous system due to any cause; severe liver, kidney or heart disease.
   Before initiating treatment, an analysis of white blood cell count and formula should be performed to ensure that only patients with normal white blood cell count receive this treatment. Weekly white blood cell counts should be performed over the first 18 weeks and subsequently every month for at least the entire duration of clozapine treatment. A white blood cell count lower than 3,500 mm³ and a neutrophil granulocytes count lower than 2,000-1,5000/mm³ will entail twice weekly white blood cell counts, and a decrease to under 3,000 white blood cells/mm³ and 1,500/mm³ neutrophils, the immediate discontinuation of treatment. Values under 2,000 white blood cells/ mm³ and 1,000 neutrophils/ mm³ indicate the need for hospitalization and haematology surveillance (table 8, annex 2).
   Patients should be advised to inform their physician on any symptom of fever or infection. Patients in whom treatment has been discontinued due to agranulocytosis should not be treated with clozapine again.
   The most frequent side effects are sedation, weight gain, hypersalivation, tachycardia, hypotension and fever; the first three are especially frequent and occur in most patients, especially in the first phase of treatment. Aside from AASEs, constipation (gastrointestinal obstruction), hypersalivation, dry mouth, nausea, vomiting, anorexia, tachycardia, ECG changes, hypertension, drowsiness, headaches, tremors, convulsions, fatigue, thermoregulation disturbance, urinary incontinence and retention, leukopenia, eosinophilia, leukocytosis; blurred vision; sweating; agranulocytosis, with less frequency; rarely dysphagia, hepatitis, cholestatic jaundice, pancreatitis, circulatory collapse, arrhythmia, myocarditis, pericarditis, thromboembolism, agitation, confusion, delirium, anaemia; very rarely, parotid hypertrophy, intestinal obstruction, cardiomyopathy, myocardial infarction, respiratory depression, priapism, interstitial nephritis, thrombocytopenia, thrombocythemia, hyperlipidemia, narrow angle glaucoma, fulminant hepatic necrosis and skin reactions.⁷³
   Clozapine is also associated with the risk of dose-related convulsive crises: 1-2% with doses below 300 mg/day, 3-4% with doses below 600 mg/day and 4-5% with doses between 600-900 mg/day.
4. Olanzapine
   This drug is chemically similar to clozapine, with moderate affinity for D₄, D₂ and 5-HT, and lower affinity for adrenergic, histamine and muscarinic receptors, acting upon positive and negative symptoms .
   It is used at 5-20 mg/day doses, with a starting dose of 10 mg. The most frequent side effects, affecting over 25 of patients, are: confusion, dry mouth, akathisia and insomnia; and, less frequently, dyspepsia, anxiety, nausea, tremors, orthostatic hypotension and diaphoresis.⁶⁹ Aside from AASEs, transient antimuscarinic effects (very rarely, quick onset of narrow angle glaucoma); drowsiness, speech disorder, exacerbation of Parkinson’s disease, abnormal gait, hallucinations, asthenia, increased appetite, increased body temperature, elevated triglyceride concentration, oedema, hyperprolactinemia (however, rare clinical manifestations), urinary incontinence; eosinophilia; less frequently, hypotension, bradycardia, photosensitivity; rarely, convulsions, leukopenia, rash; very rarely, thromboembolism, hypercholesterolemia, prolonged QT interval, hypothermia, urinary retention, priapism, thrombocytopenia, neutropenia, rhabdomyolysis, hepatitis, pancreatitis; in intramuscular form, reactions at the injection site, sinus arrest and hypoventilation.⁷³
   Doses over 10 mg/day increase the probability of extrapyramidal symptoms. It may cause worrying weight gain ranging from 3.5 to 12 kg in the high dose interval. ⁶⁹ It may temporarily elevate prolactin and liver enzymes in the first few weeks of treatment.
   It is available in oral tablets and in quick dissolution absorption form, and as an intramuscular injection.
5. Paliperidone
   It is an active metabolite of risperidone which blocks serotonergic 5HT2A, dopaminergic D₂ and adrenergic α receptors¹. It is available in extended release tablets. Dose range is 3 to 12 mg daily. The recommended dose is 6 mg taken by mouth, once a day in the morning. The most frequent side effects are headaches, and less frequently, other nervous system, cardiovascular, gastrointestinal disorders, weight gain and additional adverse reactions that have been reported for risperidone.
6. Quetiapine
   It presents affinity for 5-HT, α ₁, α ₂, H1, D₁ and D₂ receptors, thus presenting an affinity profile that differs from first and second generation (or atypical) antipsychotics.
   The average dose is 300-450 mg/day taken in two doses. The recommended starting dose is 25 mg, twice daily, then 50 mg twice daily the second day, 100 mg twice daily the third day and 150 mg twice daily the fourth day. It is an effective treatment for positive and affective symptoms, and improves cognitive function, hostility and aggressiveness. ⁸⁸
   The most frequent side effects are: sedation, dizziness, headache, insomnia, orthostatic hypotension and weight gain. All of them present low incidence.⁶⁹ There is low incidence of extrapyramidal effects⁸⁷ and there is no elevated prolactin. Aside from AASEs, drowsiness, dyspepsia, constipation, dry mouth, mild asthenia, rhinitis, tachycardia; leukocytopenia, neutrocytopenia and sometimes eosinophilia; elevated blood concentration of triglycerides and cholesterol; decreased blood concentration of thyroid hormone; possible prolonged QT interval, rarely oedema; very rarely, priapism.⁷³
   Quetiapine is available in oral tablets and long acting tablets.
7. Risperidona
   It is a potent antagonist of 5-HT2 and D₂ receptors and of adrenergic &α ₁ y α ₂ receptors to a lesser degree. 5HT2 blocking improves dopamine receptor blocking in schizophrenia. It has limited affinity for β-adrenergic and muscarinic receptors, and high affinity for α ₁ and H1. It is used to treat both positive and negative symptomsc and is well tolerated.⁷⁸
   The recommended dose is 4-6 mg/day and a single daily administration is possible due to its plasma half-life, with maintenance of effectiveness and tolerance.⁶⁹ The recommended starting dose is 2 mg once or twice a day, increasing the dose up to 4 mg on the second day in one or two doses.
   In a study that compared risperidone with clozapine in resistant patients, it was demonstrated that both drugs were equally effective, but risperidone was better tolerated, and caused less sedation and weight gain⁸⁹
   Risperidone is associated with dose-dependant extrapyramidal symptomatology, which is minimal at the therapeutic dose interval. In the initial dose adjustment period, transient orthostatic hypotension and reflex tachycardia (due to β-adrenergic activity) may develop.⁶⁹
   Infrequent side effects include sedation, erectile dysfunction, slight weight gain, decreased sexual drive, and increased prolactin (galactorrhea and menstrual disturbances). Aside from AASEs, insomnia, agitation, anxiety, headache; less frequently, dizziness, concentration disturbances, fatigue, blurred vision, constipation, nausea and vomiting, dyspepsia, abdominal pain, hyperbilirubinemia (and galactorrhea, menstrual disturbances, gynecomastia), priapism, urinary incontinence, tachycardia, hypertension, oedema, rash, rhinitis, cerebrovascular accidents, neutrocytopenia and thrombocytopenia; rarely, convulsions, hyponatremia, thermoregulation disturbances and epistaxis.⁷³
   It is available in tablets and in fast dissolving presentation and in extended release intramuscular injection (Consta).
8. Sertindole
   This drug presents affinity for 5-HT2C, 5-HT2A, D₂, α₁ and α₂ receptors, but not for histamine receptors, thus probably causing less sedation. Its antipsychotic efficacy has been proven to be superior to placebo.⁸⁷
   The most frequent side effects are: nasal congestion, postural hypotension (generally during dose escalation), sedation, tachycardia, decreased ejaculation volume in 20% of treated males (with no associated decreased libido or erectile dysfunction) and weight gain. Aside from AASEs, peripheral oedema, dry mouth, rhinitis, dyspnoea, paresthesias; rarely, convulsions, hyperglycemia.⁷³ Clinical trials show that sertindole is better tolerated than haloperidol and produces fewer extrapyramidal effects.^{69, 87} It is should be mentioned that electrocardiogram results yielded that 3% of patients treated with this drug presented prolonged QT which was greater than or equal to 500 msec without associated ventricular tachyarrhythmia, but presenting the possibility of vulnerability to develop ventricular arrhythmia (torsades des pointes), which may be fatal.^{47, 69} This possibility led to the cautionary withdrawal of this drug from the market in 1998 and later reintroduction after several favourable studies in 2006, with the recommendation to perform follow-up electrocardiograms.
   Optimum dose seems to be in the 12-20 mg/day range, with a starting dose of 4 mg/day and 4 mg increments every 4-5 days.⁶⁹
9. Ziprasidone
   This drug presents affinity for 5-HT2A receptors and moderate antagonism for D₂, strong antagonism for 5-HT1D and 5-HT2C receptors and agonism for 5-HT1A, moderate antagonism of adrenergic and histamine receptors, and minimal antagonism of muscarinic receptors. This pharmacological mechanism is associated with elevated efficacy for treating positive and negative symptoms, with minimal extrapyramidal effects and effects on prolactin.⁹⁰ It does not interact with lithium, oral contraceptives, carbamazepine, antacids or cimetidine.
   The recommended normal dose is 80 mg/day taken in two 40 mg doses when administered orally and up to 40 mg/day in up to three consecutive days when administered as intramuscular injection. The maximum dose is 160 mg/day taken in two doses.⁷³
   The most frequent side effects are: headache, drowsiness, nausea and dyspepsia. It does not produce significant weight gain and presents a low incidence of extrapyramidal effects (akathisia). It may slightly and temporarily elevate prolactin. Electrocardiogram monitoring is required due to the risk of increased QT.⁷⁸ It also present AASEs.⁷³
   Ziprasidone is presented in oral and intramuscular forms.

Frequent side effects of second generation antipsychotics

Metabolic syndrome

The metabolic syndrome refers to a group of medical disorders including obesity, hyperglycaemia and hypertriglyceridemia, usually associated with resistance to insulin. These factors can lead to ischemic cardiopathy, diabetes and diseases associated with excess weight.⁹¹
In order to diagnose metabolic syndrome, three of the following disorders must be present: a) abdominal obesity (abdominal perimeter > 102 cm in men and > 88 cm in women), b) hypertriglyceridemia (blood triglycerides > = 150 mg/dl), c) reduced high density lipoprotein cholesterol (HDLc < 40 mg/dl in men and < 50 mg/dl in women), d) high blood pressure (130/85 mmHg) or e) elevated fasting glycaemia (110 mg/dl).⁹²
It has been documented that some second generation antipsychotics, especially clozapine and olanzapine, produce significant weight gain^{93, 94} and in some cases diabetes,^95-97 which is more prevalent in schizophrenia than in the general population,⁹⁸ with the possibility to present risk factors prior to antipsychotic treatment.^{99, 100}
Hence, periodic physical follow-ups are highly advisable: blood pressure, glycaemia, and abdominal perimeter and blood cholesterol and triglyceride values.^{91, 96, 101}
Sedative, hypotensive anticholinergic effects and weight gain are frequent with all atypical antipsychotics. Clozapine is associated with an elevated incidence of anticholinergic and sedative effects, and can produce convulsions and agranulocytosis. Clozapine and olanzapine produce more weight gain and hyperglycaemia, risperidone has more extrapyramidal effects and produces higher prolactin increases and maybe QT prolongation, and quetiapine and sertindole prolong the QT interval.¹⁰²
On the other hand, a retrospective study has reported that prolonged QT interval and sudden cardiac death can be a result of both typical and atypical antipsychotics and are related with dosing.¹⁰³ The incidence of prolonged QT interval according to the results of the CATIE clinical trial (Clinical Antipsychotic Trials of Intervention) is 3%, while the incidence of sudden death in patients treated with antipsychotics is 3 per 1,000.

6.1.2. Other coadjuvant drugs

Although the APA’s CPG (2004) includes the use of other drugs to boost the therapeutic efficacy of antipsychotics and to treat residual symptoms, including positive, negative and affective symptoms, the efficacy of these treatments in patients with schizophrenia is a topic of discussion.

1. Lithium
   There is some scientific evidence that the use of lithium salts to boost antipsychotic treatment in patients with resistant symptomatology can increase antipsychotic response and reduce negative and affective symptoms. The lithium dose administered should obtain a blood concentration of 0.8-1.2 meq/l.
   The side effects of lithium are: polyuria, weight gain, cognitive disturbances, tremor, sedation, impaired coordination, gastrointestinal disturbances, hair loss, benign leukocytosis, acne and oedemas.
   The combination of an antipsychotic treatment with lithium can produce confusion and disorientation and increase the likelihood of developing the neuroleptic malignant syndrome.
2. Benzodiazepines
   These drugs may be useful in the acute phase as coadjuvant treatment for psychotic agitation, enabling a reduced dose of antipsychotics.
   Its side effects include sedation, ataxia, cognitive impairment and in some patients behavioural disinhibition. The possible abuse of these drugs should be monitored, and it should be acknowledged that the combination of these drugs with clozapine and levopromazine can be dangerous and contraindicated.^104,105
3. Anticonvulsants
   These drugs may be effective as coadjuvant treatment to antipsychotics in patients with abnormal electroencephalograms that indicate convulsive activity and in patients with agitated or violent behaviour.
   The use of carbamazepine with clozapine is not recommended due to the potential of both drugs to produce agranulocytosis.
   Carbamazepine and valproate reduce blood concentration of antipsychotics as a result of liver enzyme induction.
4. Antidepressants
   SSRIs are especially used when there is a post-psychotic depression which is difficult to differentiate from negative symptoms produced by first generation antipsychotics. Overall, evidence pointing to the efficacy of antidepressants in the treatment of negative symptoms is very moderate and most studies have been performed using first generation antipsychotics.¹⁰⁶ Two studies demonstrated the efficacy of fluvoxamine and clomipramine in the treatment of obsessive-compulsive symptoms in schizophrenia.¹⁰⁶
   Additionally, major depression and obsessive-compulsive disorder are comorbid disorders that frequently develop in patients with schizophrenia who would possibly respond to antidepressants. However, some antidepressants (those which inhibit catecholamine reuptake) can potentially maintain or exacerbate psychotic symptoms in some patients.⁴

6.1.3. General recommendations for antipsychotic treatments

International medical literature^107-114 has extensively addressed treatments with antipsychotic drugs, especially assessing their efficacy, effectiveness and side effects. Each drug has been analyzed individually as much as it has been compared to other drugs, particularly in the case of first and second generation antipsychotics. The objective of this assessment is to formulate recommendations on the use of these drugs.

A main issue for recommendations on the use of antipsychotic treatments is choosing one or another, particularly when it is a first psychotic o schizophrenic episode. When choosing medication, different criteria overlap such as the degree of response of symptoms, side effects that may develop patient preferences and administration route. All of these factors should be taken into account.

The comparison of the different CPGs selected has yielded the following general recommendations. According to the APA’s CPG, second generation antipsychotics should be the drugs of choice in acute phases, mainly because the risk of causing extrapyramidal side effects and tardive dyskinesia is lower.¹⁰⁶ The NICE’s CPG concludes that the evidence considered suggests that second generation antipsychotics are, at least, as effective as traditional drugs in terms of general response rates. There is also evidence suggesting that these drugs may vary in their relative effects on positive and negative symptoms and relapse rates. However, there is insufficient data to differentiate the assessment of the overall impact of each atypical antipsychotic for people with schizophrenia. Likewise, it determines that the conclusions that can be extracted from most studies are limited due to the lack of long-term follow-up.3,¹¹⁵ The RANZCP CPG1 considers that there is minimal evidence indicating that second generation antipsychotics are more effective than first generation antipsychotics in the acute treatment of positive symptoms, even though they seem to be more effective at preventing relapse. Available data suggest, but do not prove, greater efficacy for negative and neurocognitive symptoms. Greater importance is granted to the fact that new antipsychotics are much better tolerated and produce less motor side effects, including tardive dyskinesia.

The CPG of the Canadian Psychiatric Association² determines that there are no clear and consistent differences between first and second generation antipsychotics in relation to therapeutic response to positive symptoms, with the exception of clozapine in the treatment of resistant patients. Second generation drugs have a wider spectrum of therapeutic effects, with a small but significant effect on negative symptoms and cognitive deterioration. It also considers the significant differences between first and second generation antipsychotics in the side effects profiles.

Second generation antipsychotics produce fewer neurological side effects, both extrapyramidal side effects and tardive dyskinesia, but may also have a greater tendency to cause metabolic side effects (weight gain, dyslipidemia or metabolic syndrome), even though the evidence is based especially on clinical experience and on the publication of non-randomized studies.² Hence, the recommendation reached is to use second generation antipsychotics, particularly at the beginning of pharmacological interventions.

The Canadian CPG establishes the following general principles for pharmacological treatments: ²

1. Pharmacotherapy with antipsychotic medication is an essential component of the treatment plan for the majority of patients with schizophrenia.
2. Psychosocial interventions act synergically with drugs to optimize adherence to treatment and achieve successful community life. The use of both interventions is recommended in the treatment of the disorder.
3. Medication should be individualized because individual response to treatment is highly variable. The current problem and the patient’s prior response to pharmacotherapy should be considered, including efficacy and side effects. Patients with a first psychotic episode generally require lower doses, as do elderly patients.
4. The use of simple therapeutic guidelines, such as one daily administration, promote adherence to treatment.
5. Dosage should be maintained within the recommended range, and the reasons for altering this range should be clearly documented and justified.
6. The simultaneous use of more than one antipsychotic is not backed by available scientific evidence.
7. Regular and periodic assessments are just as necessary when patients respond to medication, when their response fails, and when they develop side effects. Standardized scales are useful tools for initial and subsequent assessments.

Moore, based on the study of five guidelines, algorithms and consensus of North American experts which include the APA’s CPG, the Expert Consensus Guideline on Treatment of Schizophrenia, el Texas Medication Algorithm Project (TMAP) Schizophrenia Algorithm, PORT and the Schizophrenia Algorithm of the International Psychopharmacology Algorithm Project has gathered the general recommendations shared by nearly all of them, and which coincide with the CPGs used in this document:¹¹⁶

1. Preferable use of second generation antipsychotics for the first episode of schizophrenia.
2. Use of clozapine after one or two failed attempts with other antipsychotics.
3. No use of combined antipsychotic drugs, except as a last resort.

The study developed by the CATIE group considers that the relative efficacy of second generation antipsychotics (atypical) in comparison with older drugs has not been addressed in depth, even though new drugs are being used more frequently. A first generation antipsychotic, perphenazine, was compared with several more recent drugs in a double blind trial. 1,493 patients with schizophrenia from 57 centres in the United States participated in this study, and were randomly assigned to the olanzapine (7.5 to 30 mg daily), perphenazine (8 to 32 mg daily), quetiapine (200 to 800 mg daily), or risperidone (1.5 to 6.0 mg daily) groups over a maximum period of 18 months. Once approved by the FDA, ziprasidone was also included (40 to 160 mg daily). The main objective consisted in defining differences in the overall efficacy of these five treatments. The study concluded that most patients in all groups dropped out of the assigned treatment due to lack of efficacy, intolerable side effects or other reasons. Olanzapine was associated with lower dropout rates. The efficacy of perphenazine was, apparently, similar to the efficacy of quetiapine, risperidone and ziprasidone. Olanzapine was associated with increased weight gain and increased glucose and lipid metabolic values. ¹¹⁷

In another study linked to the CATIE project it was determined that, after two months of antipsychotic treatment in patients with schizophrenia who were randomly assigned to pharmacological treatment with olanzapine, perphenazine, quetiapine or risperidone, all groups obtained small but significant improvements in neurocognition.¹¹⁸ No differences were detected amongst any two drugs including the atypical antipsychotic perphenazine.

Second generation antipsychotics are perceived as more effective, presenting fewer side effects and seem to be preferred by patients. However, most of the scientific evidence available derives from clinical trials on the short-term efficacy on symptoms. Hence, the CUTLASS research group (Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study) designed a controlled, randomised trial with the aim of confirming the hypothesis that in some patients with schizophrenia who require treatment changes, second generation antipsychotics, aside from clozapine, are associated with improved quality of life at one year when compared to first generation antipsychotics.¹¹⁹ This pragmatic multicenter study which did not receive funding with commercial interests assessed patients at 12, 26 and 56 weeks based on the intention to treat analysis. The main hypothesis of significantly improved quality of life after one year follow-up was refuted. Participants in the group that received first generation antipsychotics showed a tendency to improved quality of life and symptomatology. Participants did not indicate any preference for any one type of drug; costs were similar. In conclusion, people with schizophrenia that have switched medication due to clinical reasons, do not present disadvantages at one year in terms of quality of life, symptoms or care-related costs with the use of first generation drugs versus second generation drugs, excluding clozapine.

Lewis et al. developed the second part of the previously mentioned CUTLASS2 study.¹²⁰ The project design included a controlled, randomized trial that was also pragmatic, open and multicenter, and was focused on the effectiveness of clozapine versus other second generation antipsychotics in the treatment of schizophrenia. Evaluators were blind to treatment condition, the sample follow-up lasted one year and there was no funding from the pharmaceutical industry. The trial was more focused on the relative clinical efficacy of second generation antipsychotics, excluding clozapine, than on the individual efficacy of each drug, given that these drugs are generally grouped together in clinical guidelines. The authors determined that in patients with schizophrenia who respond poorly to treatment with two or more antipsychotic drugs, there is scientific evidence supporting initiating treatment with clozapine instead of other second generation antipsychotic drugs from the point of view of improved symptoms over one year.

Results were mirrored in the CATIE and CUTLASS studies, and surprised both groups of researchers. In both trials, the main hypothesis was refuted and second generation antipsychotics were not proven to be more effective (with the exception of olanzapine in the CATIE study). Furthermore, these drugs did not produce fewer extrapyramidal side effects. In both trials, clozapine was the most effective drug for treatment-resistant patients.¹²⁰

A meta-analysis of 150 double-blind studies (most of them short-term) with a total of 21,533 patients with schizophrenia was recently published comparing the efficacy of different antipsychotics versus haloperidol.⁸⁵ Given the uncertainties regarding the supposed superiority of second generation antipsychotics to first generation antipsychotics, a meta-analysis of clinical trials was conducted with the aim of comparing the effects of these two types of drugs in patients with schizophrenia. Nine second generation antipsychotics were compared with first generation antipsychotics with several variables: overall efficacy (primary endpoint), positive symptoms, negative symptoms, depressive symptoms, relapses, quality of life, extrapyramidal effects, weight gain and sedation. It was determined that second generation antipsychotics differ from each other in many properties and are not a homogeneous group. This meta-analysis provides information to individualize treatment based on efficacy, side effects and cost.

On the other hand, when research is focused on first psychotic episodes a certain short term advantage is observed in terms of effectiveness for second generation antipsychotics versus first generation drugs, as is described below.

A double blind, randomized clinical trial compared the efficacy of olanzapine versus haloperidol in acute phase in patients with a first psychotic episode.¹¹² At 12 weeks of treatment, psychopathological, psychosocial, neurocognitive, and brain morphology and functioning measures were taken. As was observed in other studies, olanzapine and haloperidol were both effective at reducing acute psychopathological symptomatology of the first psychotic episodes. However, olanzapine presented several advantages in its therapeutic response. Specifically, patients treated with olanzapine presented a greater reduction of symptomatological severity and a lower rate of treatment-induced Parkinsonism and akathisia. Additionally, permanence in the study was higher with olanzapine. It should be noted that permanence in the study in this type of population is important due to its high relapse risk. The authors indicate the need for long-term results in order to determine if atypical antipsychotics really are better in a first psychotic episode.

Following in this line, in the year 2005 Schooler et al. performed a study on the long term efficacy of risperidone versus haloperidol in patients with a first psychotic episode.¹²¹ They designed a double-blind randomized study comprised of a sample of 555 patients who were administered flexible doses of the aforementioned drugs. The authors observed that relatively low doses of antipsychotic drugs lead to significant symptomatic improvement in most patients with a first psychotic episode. AT long-term, risperidone prevented relapse in a greater number of patients and for a longer peiod of time and, also, caused less abnormal movements than haloperidol.

Later, McEvoy et al. conducted a study to assess the effectiveness of olanzapine, quetiapine and risperidone in patients in an early phase of psychosis.¹²² Patients were randomly assigned to one of the following pharmacological treatment conditions: 1) olanzapine, 2) quetiapine and 3) risperidone. The authors studied the rates of treatment interruption over a period longer than 52 weeks and determined that olanzapine, quetiapine and risperidone showed comparable efficacy in patients with incipient psychotic disorder, as was evidenced by similar treatment interruption rates in the different study conditions.

Schooler conducted a systematic review of the literature published between 1975 and 2006 on the short- and long-term efficacy of conventional and atypical antipsychotic drugs in patients with a first episode of schizophrenia with the aim of determining strategies to improve treatment adherence in this population.¹²³ A total of 17 studies that met the established inclusion criteria were selected, and after review, the author concluded that atypical antipsychotic drugs present advantages in the long-term management of a first episode of schizophrenia. Futhermore, it was emphasized that long-term use of atypical antipsychotics could be considered a new strategy in patients with a first episode of schizophrenia.

More recently, Opjordem et al. elaborated a naturalistic study with the aim of comparing treatment interruption rates with first generation antipsychotic versus second generation antipsychotics in patients with a first psychotic episode.¹²⁴ To do so, they considered the prescription of these drugs in 301 patients with a first psychotic episode from four recruitment areas. During the first year of study, the first pharmacological option was low-dose first generation antipsychotics. At the second year, second generation antipsychotics were considered the first option. A switch of treatment was allowed when any of the drugs were deemed to be ineffective or triggered significant side effects. This switch was more frequent in the group treated with low-dose first generation antipsychotics than in the group treated with second generation antipsychotics. The lack of therapeutic effect and the presence of side effects were the most common reasons for a switch of treatment in the group of patients who received first generation antipsychotics. Furthermore, this group of patients reported the presence of akathisia, Parkinsonism, dyskinesia, dystonia and dysphoria more frequently. On the other hand, patients who received second generation antipsychotics reported weight gain and sedation as the most frequent side effects. Results point to better adherence and tolerability of second generation antipsychotics versus low-dose first generation antipsychotics.

In conclusion, decision-making regarding the use of antipsychotic drugs seems to be conditioned by three main factors. Firstly, the similarities of both antipsychotic groups’ therapeutic effects on positive symptoms, which are the ones that usually lead to the initiation of pharmacological treatment. Secondly, the different profiles of side effects that they can produce, and which are deemed to be the main cause of poor adherence to treatment. And finally, the patient’s preference towards one specific drug or presentation. Hence, it can be concluded that antipsychotic treatment should be individualized.

On these grounds, the following section presents a series of recommendations on pharmacological interventions with antipsychotics, accompanied by a Pharmacological Intervention Algorithm (annex 2).