Clinical Effectiveness and Safety Profile of Lithium-Antipsychotic and Valproate-Antipsychotic Combinations in Bipolar Disorder: A Narrative Review

Bipolar disorder is a chronic psychiatric condition characterized by recurrent mood episodes that may impair daily functioning and require long-term pharmacological treatment. Combination therapy involving mood stabilizers and second-generation antipsychotics (SGAs) is commonly used in the management of bipolar disorder, particularly lithium-SGA and valproate-SGA combinations. This narrative review aimed to analyze and compare the clinical effectiveness, functional outcomes, and safety profiles of these two combinations in patients with bipolar disorder. A literature search was conducted using PubMed, ScienceDirect, and Scopus for articles published between 2016 and 2026. Of the 2,482 articles identified, 31 met the initial selection criteria, and seven were subsequently included in this review. The findings indicated that both lithium-SGA and valproate-SGA combinations provided clinical benefits in controlling manic symptoms and preventing mood episode recurrence, although their effectiveness varied according to the treatment phase. Lithium-SGA combinations demonstrated benefits in the management of acute manic and mixed episodes. However, evidence regarding functional outcomes remained limited and varied across studies. Both combinations also presented distinct safety considerations. Therefore, treatment selection should be individualized according to the patient's clinical condition, therapeutic goals, expected treatment response, safety profile, and monitoring requirements. In conclusion, both combinations may serve as therapeutic options for bipolar disorder, with their selection requiring careful consideration of the potential clinical benefits and associated risks. ABSTRAK Gangguan bipolar merupakan gangguan psikiatri kronis yang ditandai dengan episode perubahan suasana hati berulang, sehingga dapat mengganggu fungsi sehari-hari dan memerlukan pengobatan farmakologis jangka panjang. Kombinasi penstabil suasana hati dengan antipsikotik generasi kedua (second-generation antipsychotics/SGA) sering digunakan dalam penatalaksanaan gangguan bipolar, terutama kombinasi lithium-SGA dan valproat-SGA. Tinjauan naratif ini bertujuan untuk menganalisis dan membandingkan efektivitas klinis, luaran fungsional, serta aspek keamanan kedua kombinasi tersebut pada pasien gangguan bipolar. Penelusuran literatur dilakukan melalui basis data PubMed, ScienceDirect, dan Scopus terhadap artikel yang diterbitkan pada periode 2016–2026. Dari 2.482 artikel yang teridentifikasi, sebanyak 31 artikel memenuhi kriteria seleksi awal, kemudian tujuh artikel dipilih untuk dianalisis dalam tinjauan ini. Hasil menunjukkan bahwa kombinasi lithium-SGA dan valproat-SGA sama-sama memberikan manfaat klinis dalam mengendalikan gejala mania dan mencegah kekambuhan episode suasana hati, meskipun efektivitasnya dapat berbeda berdasarkan fase pengobatan. Kombinasi lithium-SGA menunjukkan manfaat pada penanganan episode mania akut dan episode campuran. Namun, bukti mengenai luaran fungsional masih terbatas dan menunjukkan hasil yang bervariasi. Kedua kombinasi juga memiliki pertimbangan keamanan yang berbeda sehingga pemilihan terapi perlu disesuaikan dengan kondisi klinis pasien, tujuan pengobatan, respons yang diharapkan, profil keamanan, serta kebutuhan pemantauan. Dengan demikian, pemilihan kombinasi lithium-SGA atau valproat-SGA harus dilakukan secara individual berdasarkan pertimbangan manfaat dan risiko terapi.