Antidepressant-Acting Antipsychotics
(Neuroleptic)

Antidepressant-acting antipsychotics, also known as add-on atypical antipsychotics or dopaminergic antidepressant agents or neuroleptic, are a group of drugs originally developed to treat psychotic disorders but which have shown significant antidepressant efficacy in specific clinical contexts. Unlike traditional antidepressants, these agents target a broader range of neurotransmitter systems, particularly modulating dopamine, serotonin, and to a lesser extent, norepinephrine.

Their use in depression has increased considerably in recent years, especially in cases of treatment-resistant major depression, bipolar depression, and in patients with psychotic features or marked somatization. Some of these agents have received regulatory approval (FDA, EMA) as adjunctive treatments for patients who do not adequately respond to antidepressant monotherapy.

Mechanism of Action

These antipsychotics exert their antidepressant effects by modulating mesolimbic and mesocortical dopaminergic activity, improving symptoms such as apathy, anhedonia, psychomotor slowing, and treatment resistance. Many also act as partial agonists or antagonists at serotonin receptors (5-HT2A and 5-HT1A), contributing to the reduction of anxiety and depressive symptoms.

Depending on the molecule, the antidepressant effect may be:

• Direct: as in low-dose amisulpride or levosulpiride, which act on presynaptic dopamine receptors;
• Complementary: as in aripiprazole, quetiapine, or olanzapine, used as add-on therapy to enhance the efficacy of antidepressants in non-responders.

It is important to note that these drugs do not replace conventional antidepressants, but rather complement or potentiate their action in selected clinical scenarios. Agents such as low-dose aripiprazole and quetiapine have received formal approval for treatment-resistant unipolar depression as adjunctive therapy.

Aripiprazole

Aripiprazole is a partial agonist at dopamine D2 and serotonin 5-HT1A receptors, and an antagonist at 5-HT2A. This modulating—rather than purely blocking—effect allows it to stabilize dopaminergic activity bidirectionally: decreasing it in hyperactive states (as in psychosis) and increasing it in areas where it is deficient, such as in depression. For this reason, it is one of the few antipsychotics approved by the FDA as add-on treatment for treatment-resistant major depression.

It is particularly effective in patients with apathy, anhedonia, and persistent negative symptoms following conventional antidepressant therapy. Its augmentation efficacy is well-documented even at low doses (2.5–10 mg/day). Side effects may include insomnia, restlessness (akathisia), tremor, and occasionally weight gain. Its metabolic profile is generally more favorable compared to other atypical antipsychotics.

Quetiapine

Quetiapine is an atypical antipsychotic with strong sedative and antidepressant properties, attributed to its antagonism at 5-HT2A, D2, H1, and alpha1 receptors, and the formation of an active metabolite (norquetiapine) that functions as a norepinephrine reuptake inhibitor (NET). The extended-release (XR) formulation is approved for bipolar depression and as an adjunct in treatment-resistant unipolar depression.

It is particularly indicated in patients with mixed features, severe anxiety, sleep disturbances, or mild psychotic symptoms. The standard antidepressant dose ranges from 50 to 300 mg/day. Common side effects include sedation, increased appetite and weight gain, orthostatic hypotension, and fatigue. It may also elevate cholesterol and triglyceride levels, requiring periodic metabolic monitoring.

Olanzapine

Olanzapine is a multi-receptor antagonist with affinity for dopaminergic, serotonergic, histaminergic, and cholinergic receptors. Its use in depression is generally reserved for psychotic, mixed, or highly resistant forms. The olanzapine-fluoxetine combination (OFC) is approved in the United States for bipolar depression and, in some cases, for non-responsive major depression.

It effectively reduces agitation, irritability, and psychotic features in depressive episodes. However, its use is limited by an unfavorable metabolic profile, with a high risk of weight gain, dyslipidemia, and insulin resistance. Monitoring of weight, blood glucose, lipids, and liver function is essential. Effective doses range from 5 to 20 mg/day, either alone or in combination.

Amisulpride

Amisulpride, a substituted benzamide antipsychotic, exhibits a pronounced antidepressant effect at low doses (50–100 mg/day), due to selective blockade of presynaptic D2 and D3 dopamine receptors, enhancing dopamine release in the mesocortical system. At antipsychotic doses (above 400 mg/day), postsynaptic blockade predominates, with sedative and antipsychotic effects.

It is particularly effective in anergic depression or psychomotor retardation, even in patients unresponsive to serotonergic antidepressants. Amisulpride is generally well tolerated, although it may cause hyperprolactinemia, menstrual irregularities, and asthenia. It lacks significant anticholinergic or sedative effects, making it suitable for elderly patients.

Levosulpiride

Levosulpiride is the active enantiomer of sulpiride and also belongs to the substituted benzamide class. It selectively blocks presynaptic D2 receptors, enhancing dopaminergic transmission in limbic and cortical areas. At low doses (25–50 mg/day), it exerts antidepressant, anxiolytic, and prokinetic gastrointestinal effects.

It is mainly used in somatized depressive syndromes, mild depression with gastrointestinal symptoms (e.g., nausea, epigastric fullness, dyspepsia), and in patients with pronounced hypochondriasis. Although frequently prescribed in non-psychiatric settings, it is not included in official guidelines for major depression. Side effects include galactorrhea, amenorrhea, elevated prolactin levels, and possible extrapyramidal symptoms in sensitive individuals or at higher doses.

Clinical Indications and Use

Antidepressant-acting antipsychotics are not first-line treatments for major depression but are useful in specific clinical scenarios, often in combination with conventional antidepressants. The main indications include:

• Treatment-resistant depression: in patients unresponsive to two or more adequate antidepressant trials, agents such as aripiprazole, quetiapine XR, and olanzapine may be added as augmentation;
• Bipolar depression: quetiapine and the olanzapine-fluoxetine combination are approved for bipolar depressive episodes;
• Depression with psychotic features: olanzapine or quetiapine are used to control delusional thinking or hallucinations in severe depressive episodes;
• Depression with strong somatization: amisulpride and levosulpiride are helpful in cases with psychomotor slowing, functional gastrointestinal complaints, and hypochondria.

Their use should be supervised by specialists, due to the complex pharmacology and need for close monitoring of side effects.

Clinical Management and Monitoring

Treatment with antipsychotics requires careful risk-benefit assessment, particularly regarding metabolic, neurological, and endocrine adverse effects. Key elements to monitor include:

• Body weight, BMI, blood glucose, lipid profile: to be checked at baseline and periodically during treatment, especially with olanzapine and quetiapine;
• Prolactin levels: especially with amisulpride and levosulpiride due to risk of hyperprolactinemia and related symptoms;
• Extrapyramidal symptoms: rare but possible, particularly at higher doses or in susceptible patients;
• Liver function and QTc interval on ECG: recommended in long-term therapy or in patients with comorbidities.

Patients should be informed of the off-label use of some agents in depressive disorders, and an ongoing dialogue should be established to monitor efficacy, tolerability, and adherence.

Final Considerations

Antipsychotics with antidepressant activity represent a valuable resource in cases of treatment-resistant, somatized, or bipolar depression. Their modulation of dopaminergic and serotonergic pathways enables treatment of symptoms that are often unresponsive to conventional antidepressants, such as anergia, apathy, and persistent somatic complaints.

However, their use requires clinical expertise and careful monitoring, particularly concerning metabolic and neuroendocrine risks. When properly selected and managed, these agents can significantly improve clinical outcomes and quality of life for patients who would otherwise remain treatment-refractory.

Summary Table

References
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