Mania During Depression Treatment: What It Means and Why It Happens

Introduction

Depression is a mood disorder characterized by persistently low mood, sadness, slowed thinking, lack of energy, as well as slowed movements and speech (Table 1). For a clinical diagnosis, typical symptoms of depression (at least 5 out of 9) must persist for longer than 2 weeks.

In some cases, during the treatment of a patient with depression, manic symptoms may emerge (Table 2). An improvement in mood during antidepressant therapy may indicate effective treatment, adverse effects of medication, previously undiagnosed Bipolar Affective Disorder (BAD), or a transition from depression to mania in the context of BAD.

Therefore, the physician faces several important clinical questions: does the onset of mania indicate BAD? Or could the manic symptoms have been triggered by prescribed antidepressants, other medications, or their combinations? Could these symptoms be related to another underlying condition, or possibly to the use of psychoactive substances?

It is also essential to differentiate whether the observed symptoms represent true mania, severe anxiety, akathisia, or the effects of stimulant substances. Additionally, it must be considered whether the manic symptoms will resolve after discontinuation of the suspected medications, whether further investigations are required (such as neurological assessment or brain imaging studies (Table 3)), and whether treatment for mania should be initiated — including decisions about timing, choice of medication, and appropriate dosing.

Table 1. Symptoms of Depression

Typical Symptoms • Persistently low mood and sadness for most of the day, nearly every day • Decreased interest and ability to experience pleasure • Reduced energy and activity levels, increased fatigue Other Common Symptoms • Impaired concentration • Decreased self-esteem and self-confidence • Feelings of guilt and worthlessness • Pessimistic outlook on the future • Suicidal thoughts or actions • Sleep disturbances • Decreased appetite (although in some cases it may be increased) Somatic Symptoms • Loss of interest and pleasure in previously enjoyable activities • Reduced emotional responsiveness to previously pleasant stimuli • More pronounced depressive symptoms in the morning • Early morning awakening (several hours earlier than usual) • Objective signs of psychomotor retardation or agitation • Physical pain (commonly headaches, abdominal or chest pain) • Significant decrease in appetite • Weight loss • Decreased libido Psychotic Symptoms (in severe depression) • Delusional ideas — most commonly involving themes of guilt, poverty, or inevitable misfortune • Hallucinations — typically olfactory (unpleasant smells such as decay or rotting) and auditory (accusatory or blaming voices)

  Table 2. Symptoms of Mania

Typical Symptoms • Elevated mood (often not corresponding to circumstances), frequently accompanied by irritability or aggressiveness • Increased self-esteem, grandiosity, inappropriate optimism, and excessive familiarity • Increased energy and activity levels • Decreased need for sleep • Accelerated thinking and speech • Impaired concentration • Tendency toward risky or dangerous activities (e.g., reckless driving, casual sexual behavior, excessive spending) • Significant impairment in occupational, family, and social functioning Other Symptoms That May Occur • Dysphoria • Presence of some depressive symptoms • Suspiciousness • Delusions (most commonly of grandeur or persecution) • Hallucinations

  Table 3. Tests for First-Time Mania Presentation

Test	Purpose
Toxicology screening	To assess possible substance use or abuse
Thyroid function tests	To evaluate for hyperthyroidism or hypothyroidism
Neuroimaging studies	Indicated in cases of head trauma history, presence of focal neurological symptoms, or in elderly patients
Electroencephalography	Recommended when seizures, cognitive impairment, neurological or motor symptoms, or atypical manic features are present
Lumbar puncture	Indicated in cases of delirium of unknown origin, suspected central nervous system infection, or presence of meningeal signs

Tests for Infectious Diseases

Tests for infectious diseases (e.g., Lyme disease antibodies, human immunodeficiency virus) should be performed if indicated by the patient’s medical history and clinical examination

Discontinuation of Antidepressants

Mania or mood elevation beyond normal limits during antidepressant treatment has been observed for decades, since the 1950s, when imipramine therapy was first introduced. However, it remains unclear whether this mood elevation is caused by the underlying disease itself or triggered by antidepressant use.

Once mania develops, antidepressants tend to exacerbate symptoms. Nevertheless, observational studies (EMBLEM, 2010) show that approximately 15% of patients presenting with manic symptoms continue to receive antidepressants. Evidence suggests that antidepressants not only fail to provide benefit in such cases but may worsen the clinical course, especially in mixed episodes, and do not prevent the occurrence of manic depression.

Discontinuation of antidepressants can help reduce symptoms of mania or mixed episodes. Even when clear manic symptoms are present, antidepressants — particularly selective serotonin reuptake inhibitors (SSRIs), often used during short remission phases — should be discontinued gradually, with dose reduction, in order to avoid withdrawal symptoms.

Medications for Treating Mania

Lithium and valproates (mood stabilizers) remain the standard treatment for acute mania. The use of valproates increased significantly in the 1990s, largely due to their faster onset of action compared to lithium.

In clinical practice, patients with mania are also widely treated with classical (typical, first-generation) antipsychotic drugs. However, for a more rapid therapeutic effect and a lower risk of side effects, atypical antipsychotics are now often preferred.

For patients experiencing severe manic episodes who are cooperative and able to take medication, lithium or valproates may be prescribed. The choice of treatment depends on symptom severity and behavioral disturbances.

In cases of acute agitation or aggression, classical antipsychotics are generally preferred. Although controlled studies have demonstrated the effectiveness of atypical antipsychotics in mild to moderate mania, their efficacy in severe mania remains less certain. In addition, there is limited clinical experience regarding optimal dosing, and higher doses may increase the risk of QT interval prolongation.

Currently, atypical antipsychotics are considered more suitable for the treatment of mild mania and hypomania. An exception is clozapine, which has shown effectiveness in treatment-resistant mania, including cases with both euphoric and dysphoric features.

Factors Influencing Treatment Choice

When selecting a mood stabilizer or another medication, the following factors should be considered:

• Predominant type of affective episodes (mania/hypomania vs. depression)
• Severity and frequency of episodes
• Associated psychopathological symptoms
• Whether previous episodes were related to antidepressant use
• Long-term tolerability and prognosis of treatment
• Patient’s preferences and opinion

Course and Recovery

Functional recovery after a manic episode is a prolonged process that continues even as symptoms gradually decrease or disappear. Subsyndromal symptoms often persist after the acute episode.

Some authors report that the average duration of a manic episode is approximately 13 weeks. It is essential for both the patient and their family members to understand that recovery is gradual and long-lasting. This understanding improves treatment adherence and helps patients better adjust their daily life, studies, and work plans.

Table 4. Clinical Circumstances Influencing Drug Choice in Mania

Drug	Clinical Circumstances
Lithium	Preferable: when starting mania only; if it is only mania (vs. mixed episodes) Worth considering for patients whose relatives with bipolar affective disorder were effectively treated with lithium
Valproates	More effective when the disease presents with both manic and depressive symptoms; during recurrent episodes; if the patient is prone to alcohol or other substance abuse If there is impulsivity, a tendency towards aggression
Carbamazepine	More suitable than lithium in cases of mixed episodes; if the patient is prone to alcohol or other substance abuse No effect on weight Liver function, blood counts should be monitored No final conclusions on its effectiveness in treating depression during bipolar affective disorder and for relapse prevention
Topiramate	Often referred to as a mood stabilizer; however, its effectiveness during acute mania has not been proven May be useful as an adjunctive medication in treating mania to reduce the risk of relapse, polarity	Atypical Antipsychotics	Meta-analysis did not show significant differences between individual drugs in this group; larger differences may be due to drug tolerability No comparative data on drug safety and efficacy during the first mania episode were provided	Benzodiazepines	Useful adjunctive medications to suppress agitation; for insomnia

 

Summary

If a patient with depression who is being treated with antidepressants begins to exhibit symptoms of mania or hypomania, antidepressant therapy should be discontinued. To stabilize the condition, treatment with mood stabilizers or atypical antipsychotics (or a combination of both) should be initiated promptly.

It is essential to collect a detailed medical history, perform the necessary diagnostic tests, and arrange appropriate consultations in order to exclude other possible causes of mania and to refine the diagnosis.

After the acute phase of mania has subsided, medications for long-term maintenance therapy should be selected, taking into account the most effective combinations for relapse prevention.

Close cooperation between the patient and their family plays a crucial role in ensuring successful treatment outcomes.

Prepared by Dr. Alvyda Pilkauskienė

Mental Health Day Hospital, Dainava Polyclinic, Kaunas City Polyclinic

REFERENCES

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"Internistas" No.10, 2018