Atypicals are less likely than haloperidol—the most widely used typical antipsychotic—to cause extrapyramidal motor control disabilities in patients such as unsteady Parkinson's disease–type movements, body rigidity, and involuntary tremors.

It has been argued that a more nuanced view, matching the properties of individual drugs to the needs of specific patients is preferable.

[3] While the atypical (second-generation) antipsychotics were marketed as offering greater efficacy in reducing psychotic symptoms while reducing side effects (and extrapyramidal symptoms in particular) than typical medications, the results showing these effects often lacked robustness, and the assumption was increasingly challenged even as atypical prescriptions were soaring.

[22][23] In 2005 the US government body NIMH published the results of a major independent (not funded by the pharmaceutical companies) multi-site, double-blind study (the CATIE project).

The authors noted an apparent superior efficacy of olanzapine to the other drugs in terms of reduction in psychopathology and rate of hospitalizations, but olanzapine was associated with relatively severe metabolic effects such as a major weight gain problem (averaging 9.4 lbs over 18 months) and increases in glucose, cholesterol, and triglycerides.

Clinically, this still appears as the minimal effective dose achieving maximal response without significant parkinsonism despite >90% receptor occupancy.

[31]In bipolar disorder, SGAs are most commonly used to rapidly control acute mania and mixed episodes, often in conjunction with mood stabilizers (which tend to have a delayed onset of action in such cases) such as lithium and valproate.

[32] SGAs are also used to treat other aspects of the disorder (such as acute bipolar depression or as a prophylactic treatment) as adjuncts or as a monotherapy, depending on the drug.

[41][42] Aripiprazole, brexpiprazole, cariprazine, olanzapine, and quetiapine have been approved as adjunct treatment for MDD by the FDA in the United States.

[46] The U.S. Food and Drug Administration requires that all atypical antipsychotics carry a black box warning that the medication has been associated with an increased risk of mortality in elderly patients.

It is not clear if atypical antipsychotics, having been in use for a relatively short time, produce a lower incidence of tardive dyskinesia.

[54] Kabinoff and colleagues (2003) found that the increase in cardiovascular disease is seen regardless of the treatment received, and that it is instead caused by many different factors such as lifestyle or diet.

In April 2005, the US Food and Drug Administration (FDA) issued an advisory and subsequent black box warning regarding the risks of atypical antipsychotic use among elderly patients with dementia.

[57] Subsequent research reports confirmed the mortality risks associated with the use of both conventional and atypical antipsychotics to treat patients with dementia.

One hypothesis as to why atypicals have a lower risk of tardive dyskinesia is because they are much less fat-soluble than the typical antipsychotics and because they are readily released from D2 receptor and brain tissue.

[66] The general consensus is that clozapine and olanzapine are associated with the greatest effects on weight gain and decreased insulin sensitivity, followed by risperidone and quetiapine.

[66] The mechanism of these adverse effects is not completely understood but it is believed to result from a complex interaction between a number of pharmacologic actions of these drugs.

Some of the newer agents, however, such as risperidone and its metabolite paliperidone, ziprasidone, lurasidone, aripiprazole, asenapine and iloperidone, have clinically insignificant effects on the M3 receptor and appear to carry a lower risk of insulin resistance.

Whereas clozapine, olanzapine and quetiapine (indirectly via its active metabolite, norquetiapine) all antagonise the M3 receptor at therapeutic-relevant concentrations.

[68] The two atypical antipsychotics with trials showing that had a low incidence of weight gain in large meta-analysis were lurasidone and aripiprazole.

[54] Kabinoff et al. suggest that there is insufficient data from large studies to demonstrate a consistent or significant difference in the risk of insulin resistance during treatment with various atypical antipsychotics.

[54] Prescribing topiramate, zonisamide, metformin, GLP-1 receptor agonists, or nizatidine alongside an antipsychotic significantly reduces weight gain.

[73] Despite increasing some risk factors, SGAs are not associated with excess cardiovascular mortality when used to treat serious psychiatric disorders.

[81] The atypical antipsychotics integrate with the serotonin (5-HT), norepinephrine (α, β), and dopamine (DA) receptors in order to effectively treat schizophrenia.

If prolactin levels become high enough, hyperprolactinaemia may occur, resulting in sexual dysfunction, weight gain, more rapid demineralization of bones, and possibly galactorrhea and amenorrhea.

[Stahl AP Explained 1 - 3] Furthermore, 5-HT2A receptor antagonism blocks the serotonergic excitation of cortical pyramidal cells, reducing glutamate release, which in turn lowers hyperactive dopaminergic D2 receptor activity in the mesolimbic pathway, reducing or eliminating the positive symptoms of schizophrenia.

[non-primary source needed] Blockade of the 5-HT2C receptor increases serotonin, releasing norepinephrine and dopamine within the brain.

Following research indicating its effectiveness in treatment-resistant schizophrenia and the development of an adverse event monitoring system, clozapine re-emerged as a viable antipsychotic.

In the past, most researchers have agreed that the defining characteristics of atypical antipsychotics are the decreased incidence of extrapyramidal side effects (EPS)[132] and an absence of sustained prolactin elevation.

Some healthcare professionals reported avoiding the name "atypical antipsychotic" when prescribing the drug to patients who had bipolar disorder.